Jak inhibitor compound and use thereof

ABSTRACT

The present disclosure relates to a class of JAK inhibitor compounds and uses thereof. Specifically, the present disclosure discloses a compound represented by formula (G), isotopically labeled compound thereof, or optical isomer thereof, geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof. The present disclosure also relates to the application of the compounds in medicine.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of International Application No.PCT/CN2020/076231, filed on Feb. 21, 2020, which claims priority toChinese Patent Application No. 201910877661.5, filed on Sep. 17, 2019and priority to Chinese Patent Application No. 201910137984.0, filed onFeb. 25, 2019, all of which are incorporated herein by reference intheir entireties.

TECHNICAL FIELD

The present disclosure provides a class of novel compounds withpharmacological activity, which can be used to inhibit Janus kinase(JAK). The present disclosure also relates to a composition comprisingthe compound, and use of the compound and the composition in thepreparation of a medicament for the treatment and/or prevention ofJAK-related diseases or disorders.

BACKGROUND

Protein kinases are a family of enzymes that catalyze phosphorylation ofspecific residues in proteins, and are broadly classified into tyrosineand serine/threonine kinases. Inappropriate kinase activities caused bymutations, overexpression or inappropriate regulation, abnormalregulation or dysregulation, and excessive or insufficient production ofgrowth factors or cytokines are involved in many diseases, including butnot limited to cancers, cardiovascular diseases, allergies, asthma andother respiratory diseases, autoimmune diseases, inflammatory diseases,bone diseases, metabolic disorders and neurological andneurodegenerative disorders (such as Alzheimer's disease). Inappropriatekinase activity triggers a variety of biological cell responsesassociated with cell growth, cell differentiation, cell function,survival, apoptosis, and cell motility related to the aforementioneddiseases and other related diseases. Therefore, protein kinases havebecome an important class of enzymes as targets for therapeuticintervention. In particular, the JAK family of cellular protein tyrosinekinases plays an important role in cytokine signal transduction(Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al., Genome Biology2004, 5, 253).

Since the first JAK inhibitor was discovered in the early 1990s, thedevelopment of JAK inhibitors has gone through nearly 30 years. JAK is afamily of intracellular non-receptor tyrosine kinases, which plays animportant role in cytokine receptor signaling pathway by interactingwith signal transducer and activator of transcription (STAT). JAK/STATsignaling pathway is involved in many important biological processessuch as cell proliferation, differentiation, apoptosis and immuneregulation. Compared with other signal pathways, the transmissionprocess of this signal pathway is relatively simple. It is mainlycomposed of three components, namely tyrosine kinase associatedreceptor, tyrosine kinase JAK, signal transducer and activator oftranscription STAT.

Many cytokines and growth factors transmit signals through the JAK-STATsignal pathway, including interleukins (such as IL-2 to IL-7, IL-9,IL-10, IL-15, IL-21, and the like), GM-CSF (granulocyte/macrophagecolony stimulating factor), GH (growth hormone), EGF (epidermal growthfactor), PRL (prolactin), EPO (erythropoietin), TPO (thrombopoietin),PDGF (platelet derived factors) and interferons (including IFN-α, IFN-β,IFN-γ and the like) and so on. These cytokines and growth factors havecorresponding receptors on the cell membrane. The common feature ofthese receptors is that the receptor itself does not have kinaseactivity, but its intracellular segment has a binding site for tyrosinekinase JAK. After the receptor binds to a ligand, tyrosine residues ofvarious target proteins are phosphorylated by activation of JAK thatbinds to the receptor to realize signal transfer from the extracellularto the intracellular.

JAK is a cytoplasmic tyrosine kinase that transduces cytokine signalsfrom membrane receptors to STAT transcription factors. As mentionedabove, JAK is the abbreviation of Janus kinase in English. In Romanmythology, Janus is the double-faced god in charge of the beginning andthe end. The reason why it is called Janus kinase is that JAK canphosphorylate cytokine receptors that it binds to, and alsophosphorylate multiple signal molecules containing specific SH2 domains.The JAK protein family includes 4 members: JAK1, JAK2, JAK3, and TYK2.They have 7 JAK homology domains (JH) in structure in which the JH1domain is a kinase domain having the function of encoding kinaseproteins; JH2 domain is a “pseudo” kinase domain, which regulates theactivity of JH1; and JH3-JH7 constitute a four-in-one domain, whichregulates the binding of JAK proteins to receptors.

STAT is a type of cytoplasmic protein that can bind to DNA in theregulatory region of target genes, and is a downstream substrate of JAK.Seven members of the STAT family have been discovered, namely STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STAT protein can bedivided into the following functional segments in structure includingN-terminal conserved sequence, DNA binding region, SH3 domain, SH2domain and C-terminal transcription activation region. Among them, thesegment of the most conserved in sequence and most important in functionis the SH2 domain, which has the same core sequence “GTFLLRFSS” as theSH2 domain of tyrosine kinase Src.

JAK-STAT signaling pathway has a wide range of functions and is involvedin many important biological processes such as cell proliferation,differentiation, apoptosis, and immune regulation. At present, theresearch related to disease and drug innovation mainly focuses oninflammatory diseases and neoplastic diseases in which the inflammatorydiseases mainly include rheumatoid arthritis, canine dermatitis,psoriasis, ulcerative colitis and Crohn's disease; and the neoplasticdiseases mainly involve myelofibrosis, polycythemia vera and primaryplatelets hyperplasia. In addition, mutations in JAK molecule itself canalso cause acute myeloid leukemia (AML), acute lymphocytic leukemia(ALL), ductal breast carcinoma and non-small cell lung cancer (NSCLC),polycythemia vera (PV), essential thrombocythemia (ET), idiopathicmyelofibrosis (IMF), chronic myeloid leukemia (CML), and the like.

JAK is a very important drug target. JAK inhibitors developed for thistarget are mainly used to screen therapeutic drugs for blood systemdiseases, tumors, rheumatoid arthritis and psoriasis. JAK-1, JAK-2 andTYK-2 are expressed in various tissue cells of human body. JAK-3 ismainly expressed in various hematopoietic tissue cells, mainly in bonemarrow cells, thymocytes, NK cells and activated B lymphocytes and Tlymphocytes. Studies have shown that JAK2 inhibitors are suitable formyeloproliferative diseases (Santos et al., Blood, 2010, 115:1131;Barosi G. and Rosti V., Curr. Opin. Hematol., 2009, 16:129; Atallah E.and Versotvsek S., 2009 Exp. Rev. Anticancer Ther. 9:663), and JAK3inhibitors are suitable as immunosuppressive agents (such as, U.S. Pat.No. 6,313,129; Borie et al., Curr. Opin. Investigational Drugs, 2003,4:1297).

Currently, JAK inhibitors approved by the FDA and EMA includeTofacitinib, Ruxolitinib, and Oclacitinib. JAK inhibitors in the middleand late stages of clinical research include Filgotinib, Peficitinib andso on.

Tofacitinib, a JAK3 inhibitor, was developed by Pfizer and was approvedby the FDA in November 2012 for the treatment of moderate to severerheumatoid arthritis (RA) due to inadequate response or intolerance tomethotrexate in adult patients. It is the first oral JAK inhibitorapproved for RA treatment. After that, it was approved by Japan PMDA forlisting in March 2013 under the trade name Xeljanz. On Mar. 16, 2017,Pfizer China announced that the CFDA had formally approved Pfizer'sapplication for the marketing of the oral JAK inhibitor. It was reportedthat the drug was approved for the treatment of adult patients withmoderate to severe rheumatoid arthritis having inadequate response orintolerance to methotrexate. At present, Tofacitinib is close to beingapproved for indications such as psoriasis, ulcerative colitis, juvenileidiopathic arthritis; and clinical trials for the treatment ofindications such as Crohn's disease and alopecia areata have alsoentered the mid- to late-stage. The main side effects of Tofacitinib areserious infection rate and increased low-density lipoprotein level. Themost common adverse effects are upper respiratory tract infection,headache, diarrhea, nasal congestion, sore throat and nasopharyngitis.In addition, it has been have reported that Tofacitinib can cause sideeffects such as anemia and neutropenia in clinical studies.

Ruxolitinib, a JAK1 and JAK2 inhibitor, was jointly developed by Incyteand Novartis and was approved by the FDA of US in November 2011. It isalso the first approved drug specifically for the treatment ofmyelofibrosis. It was approved by EMA in August 2012 and approved byJapan PMDA for listing in July 2014. The drug is sold by Incyte in theUnited States under the trade name Jakafi; and is sold by Novartis inEurope and Japan under the trade name Jakavi. Ruxolitinib is under anumber of clinical trials in the middle and late stages, wherein theindications include a variety of cancers, GVHD (rejection reaction),alopecia areata, allergic dermatitis, rheumatoid arthritis, vitiligo,psoriasis, and the like. The most common hematological adverse effectswith an incidence of >20% of Ruxolitinib are low platelet counts andanemia. The most common non-hematological adverse effects with anincidence of >10% are ecchymosis, dizziness and headache.

Olatinib, approved by the FDA of US in 2013, is used to control itchingand atopic dermatitis caused by canine allergic dermatitis. Olatinib isa new type of JAK and JAK1-dependent cytokine inhibitor. Olatinib is notonly a very effective JAK1 inhibitor, but can also inhibit the functionof JAK1-dependent cytokines in some anti-allergic, inflammation andpruritic reactions. It has little effect on cytokines that are notinvolved in activation of JAK1. Oral administration of 0.4-0.6 mg/kgOlatinib twice a day is safe and effective for the treatment of itchingcaused by allergic dermatitis. During the treatment, Olatinib canrelieve itching within 24 hours. In experiments, more than 70% ofexperimental animals (dogs) alleviated the itching response by more than50% on the 7th day. However, Olatinib cannot yet be used to treat humandiseases.

Filgotinib, a JAK1 inhibitor, passed Phase III clinical trials inSeptember 2018 for the treatment of rheumatoid arthritis. At the sametime, the study of Filgotinib for the treatment of ulcerative colitisand Crohn's disease is currently in clinical phase II/III trials.Filgotinib is a selective JAK1 inhibitor with IC50 of 10 nM, 28 nM, 810nM and 116 nM for JAK1, JAK2, JAK3 and TYK2, respectively.

Peficitinib, a JAK1 and JAK3 inhibitor, developed by Astellas, iscurrently in Phase III clinical trial for the treatment of rheumatoidarthritis. The Phase II clinical study for the treatment of psoriasishas been completed. Peficitinib is a new oral JAK inhibitor. Peficitinibinhibits the enzyme activities of JAK1, JAK2, JAK3 and TYK2 with IC50 of3.9 nM, 5.0 nM, 0.71 nM and 4.8 nM, respectively.

Although some JAK inhibitors have been approved for listing, and a largenumber of JAK inhibitors are still in clinical research, these JAKinhibitors are not satisfactory in terms of efficacy or safety.Therefore, there is always a need for JAK inhibitors with betterefficacy and/or fewer side effects.

SUMMARY

It is one object of the present disclosure to provide a novel JAKinhibitor alternative to existing JAK inhibitors, so as to provide moreoptions for the treatment of JAK-related diseases.

A further object of the present disclosure is to provide a novel JAKinhibitor with better efficacy and/or better safety than existing JAKinhibitors.

In a first aspect, the present disclosure provides a compound of Formula(G) as a JAK inhibitor

or an isotopically labeled compound thereof, or an optical isomerthereof, a geometric isomer thereof, a tautomer thereof or a mixture ofvarious isomers, or a pharmaceutically acceptable salt thereof, or aprodrug thereof, or a metabolite thereof,whereinL is C═O, O═S═O, CH₂ or a linkage; andX₁ is N or CR₁₄; andX₂ is N or CR₁₅; andX₃ is N or CR₁₆; andR₁₄, R₁₅, R₁₆ are each independently selected from H, —OH, —SH, —CN,halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl,C₅₋₇ aryl, 5-7 membered heteroaryl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂),—C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂,—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the—S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, and 3-7membered heterocycloalkyl are optionally substituted with 1, 2 or 3substitutes selected from halogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN,C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄ hydroxyalkyl, —S—C₁₋₄ alkyl, —C(═O)H,—C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄ alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄alkyl)₂, —N(C₁₋₄ alkyl)(C(═O)C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxy andC₁₋₄ haloalkoxy; andR₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —SR₁₂, —OR₁₂, —CN, halogen, —NO₂,—SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl or C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclyl, C₅₋₁₁bicycloalkyl, or 5-11 membered bicyclic heteroalkyl, and R₁₃ issubstituted with 0, 1, 2, 3 or 4 R₁(s), in which R₁₇ and R₁₈ are eachindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₅₋₇aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 memberedbicyclic heteroaryl, 11-15 membered tricyclyl, C₅₋₁₁ bicycloalkyl, and5-11 membered bicyclic heteroalkyl and are optionally substituted withone or more substitutes each independently selected from —OH, —CN, —SH,halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, 7-11 membered bicyclic heteroaryl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂),—C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂,—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the—S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, C₅₋₇aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 memberedbicyclic heteroaryl are optionally substituted with 1, 2 or 3substitutes each independently selected from halogen, —CN, —OH, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl,—N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂,—C(═O)—N(R₉)(R₁₀), —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and—OR₁₂; or R₁₇, R₁₈ and the N atom connected thereto together form a 3-14membered ring; and0, 1, 2, 3 or 4 R₂(s) are present in formula (G), and R₂ is selectedfrom H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄ alkyl, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl,—N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂,—C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂and —OR₁₂, in which the —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, and 7-11 membered bicyclic heteroaryl are each optionallysubstituted with 1, 2 or 3 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂; andR₁ is selected from H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄alkyl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₃₋₇cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl,11-15membered tricyclyl, C₅₋₁₁bicycloalkyl, 5-11 membered bicyclicheteroalkyl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀),—C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂),—S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the —S—C₁₋₄ alkyl, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, and C₁₋₈ alkoxy are optionallysubstituted with 1, 2, 3, or 4 R₃(s), and in which the C₃₋₇ cycloalkyl,3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl,C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclic heteroaryl areoptionally substituted with 1, 2, 3, or 4 R₄(s); andR₃ and R₄ are each independently selected from H, halogen, —OH, —NO₂,—CN, —SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclicheteroaryl, —N(R₅)(R₆), —N(R₁₁)(C(═O)R₁₂), —CON(R₇)(R₈), —C(═O)—R₁₂,—C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂and —OR₁₂, in which the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-10 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, and 7-11 membered bicyclic heteroaryl are each optionallysubstituted with 1, 2, 3 or 4 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₆ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂; andR₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ are each independently H orselected from the group consisting of C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₃₋₇cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein the substituents included inthe above group are each optionally substituted with 1, 2, 3 or 4substituent(s) each independently selected from the group consisting ofhalogen, —CF₃, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, oxo, C₁₋₄ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₄ hydroxyalkyl, —S—C₁₋₄alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄ alkyl, —C(═O)—NH₂,—C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy and C₁₋₄ haloalkoxy.

In some preferred embodiments of the present disclosure, an isotopicallylabeled compound of the above-mentioned compound of formula (G) isprovided. In some more preferred embodiments of the present disclosure,an isotopically labeled compound of the compound of formula (G) isprovided, wherein all Hs are each independently and optionallysubstituted with D.

In some preferred embodiments of the present disclosure, in formula (G),X₁ is N. In some preferred embodiments of the present disclosure, informula (G), X₂ is N. In some preferred embodiments of the presentdisclosure, in formula (G), X₃ is N. In some preferred embodiments ofthe present disclosure, in formula (G), X₁ is CR₁₄, X₂ is N or CR₁₅, andX₃ is CR₁₆. In some preferred embodiments of the present disclosure, informula (G), X₁ is CR₁₄, X₂ is CR₁₅, and X₃ is CR₁₆. In some preferredembodiments of the present disclosure, in formula (G), X₁ is CR₁₄, X₂ isCR₁₅, X₃ is CR₁₆, and R₁₄, R₁₅, and R₁₆ are each independently selectedfrom H, —OH, —CN, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, and3-7 membered heterocycloalkyl. In some preferred embodiments of thepresent disclosure, in formula (G), X₁ is CR₁₄, X₂ is N, X₃ is CR₁₆, andR₁₄ and R₁₆ are each independently selected from H, —OH, —CN, halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, and 3-7 memberedheterocycloalkyl. In some preferred embodiments of the presentdisclosure, in formula (G), X₁, X₂, and X₃ are the same. In somepreferred embodiments of the present disclosure, in formula (G), X₁, X₂and X₃ are CH. In some preferred embodiments of the present disclosure,in formula (G), X₁, X₂ and X₃ are N. In some preferred embodiments ofthe present disclosure, in formula (G), X₁ is C(CH₃), X₂ and X₃ are CH.In some preferred embodiments of the present disclosure, in formula (G),X₂ is C(CH₃), X₁ and X₃ are CH. In some preferred embodiments of thepresent disclosure, in formula (G), X₃ is C(CH₃), X₁ and X₂ are CH. Insome preferred embodiments of the present disclosure, in formula (G), X₁is N, X₂ and X₃ are CH. In some preferred embodiments of the presentdisclosure, in formula (G), X₂ is N, X₁ and X₃ are CH. In some preferredembodiments of the present disclosure, in formula (G), X₃ is N, X₁ andX₂ are CH.

In some more preferred embodiments of the present disclosure, there isprovided an isotopically labeled compound of the compound of formula(G), wherein all H are each independently and optionally substitutedwith D, and X₁, X₂ and X₃ are the same. In some more preferredembodiments of the present disclosure, there is provided an isotopicallylabeled compound of the compound of formula (G), wherein all Hs are eachindependently and optionally substituted with D, and X₁, X₂ and X₃ areall CH. In some more preferred embodiments of the present disclosure,there is provided an isotopically labeled compound of the compound offormula (G), wherein all Hs are each independently and optionallysubstituted with D, and X₁, X₂ and X₃ are N. In some more preferredembodiments of the present disclosure, there is provided an isotopicallylabeled compound of the compound of formula (G), wherein all H are eachindependently and optionally substituted with D, and X₁ is C(CH₃), X₂and X₃ are both CH. In some more preferred embodiments of the presentdisclosure, there is provided an isotopically labeled compound of thecompound of formula (G), wherein all Hs are each independently andoptionally substituted with D, and X₂ is C(CH₃), X₁ and X₃ are both CH.In some more preferred embodiments of the present disclosure, there isprovided an isotopically labeled compound of the compound of formula(G), wherein all Hs are each independently and optionally substitutedwith D, and X₃ is C(CH₃), and X₁ and X₂ are both CH. In some morepreferred embodiments of the present disclosure, there is provided anisotopically labeled compound of the compound of formula (G), whereinall Hs are each independently and optionally substituted with D, and X₁is N, X₂ and X₃ are both CH. In some more preferred embodiments of thepresent disclosure, there is provided an isotopically labeled compoundof the compound of formula (G), wherein all Hs are each independentlyand optionally substituted with D, and X₂ is N, X₁ and X₃ are both CH.In some more preferred embodiments of the present disclosure, there isprovided an isotopically labeled compound of the compound of formula(G), wherein all Hs are each independently and optionally substitutedwith D, and X₃ is N, and X₁ and X₂ are both CH.

In some preferred embodiments of the present disclosure, in formula (G),L is C═O, O═S═O or CH₂. In some particularly preferred embodiments ofthe present disclosure, in formula (G), L is C═O. In some particularlypreferred embodiments of the present disclosure, in formula (G), L isO═S═O. In some particularly preferred embodiments of the presentdisclosure, in formula (G), L is CH₂. In other embodiments of thepresent disclosure, in formula (G), L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all CH, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all CH, and L is O═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all CH, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all CH, and L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all N, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all N, and L is O═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all N, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all N, and L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all CR₁₄, wherein R₁₄ is selected from—OH, —CN, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, and 3-7membered heterocycloalkyl, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all CR₁₄, wherein R₁₄ is selected from—OH, —CN, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, and 3-7membered heterocycloalkyl, and L is O═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all CR₁₄, wherein R₁₄ is selected from—OH, —CN, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, and 3-7membered heterocycloalkyl, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁, X₂ and X₃ are all CR₁₄, wherein R₁₄ is selected from—OH, —CN, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, and 3-7membered heterocycloalkyl, and L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁ is C(CH₃), X₂ and X₃ are both CH, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁ is C(CH₃), X₂ and X₃ are both CH, and L is O═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁ is C(CH₃), X₂ and X₃ are both CH, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁ is C(CH₃), X₂ and X₃ are both CH, and L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G), X₂ is C(CH₃), X₁ and X₃ are both CH, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₂ is C(CH₃), X₁ and X₃ are both CH, and L is O═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₂ is C(CH₃), X₁ and X₃ are both CH, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (G), X₂ is C(CH₃), X₁ and X₃ are both CH, and L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G), X₃ is C(CH₃), X₁ and X₂ are both CH, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₃ is C(CH₃), X₁ and X₂ are both CH, and L is O═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₃ is C(CH₃), X₁ and X₂ are both CH, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (G), X₃ is C(CH₃), X₁ and X₂ are both CH, and L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁ is N, X₂ and X₃ are both CH, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁ is N, X₂ and X₃ are both CH, and L is O═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁ is N, X₂ and X₃ are both CH, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (G), X₁ is N, X₂ and X₃ are both CH, and L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G), X₂ is N, X₁ and X₃ are both CH, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₂ is N, X₁ and X₃ are both CH, and L is O═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₂ is N, X₁ and X₃ are both CH, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (G), X₂ is N, X₁ and X₃ are both CH, and L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G), X₃ is N, X₁ and X₂ are both CH, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₃ is N, X₁ and X₂ are both CH, and L is O ═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G), X₃ is N, X₁ and X₂ are both CH, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (G), X₃ is N, X₁ and X₂ are both CH, and L is a linkage.

In some preferred embodiments of the present disclosure, in formula (G),R₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —OH, —SH, —CN, halogen, —NO₂, —SF₅,—S—C₁₋₄ alkyl, C₁₋₆ alkyl, or C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclyl,C₅₋₁₁bicycloalkyl, or 5-11 membered bicyclic heteroalkyl, in which R₁₇and R₁₈ are each independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₅₋₇ aryl, and 5-7 memberedheteroaryl, and are optionally substituted with one or more of —OH, —CN,—SH, halogen, —NO₂,— and SF₅, wherein R₁₃ is optionally substituted with1, 2, 3 or 4 R₁(s). In some preferred embodiments of the presentdisclosure, in formula (G), R₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —OH,—SH, —CN, halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, or C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11membered bicyclic heteroaryl, or11-15 membered tricyclyl and R₁₇ and R₁₈ are defined as above, whereinR₁₃ is optionally substituted with 1, 2, 3 or 4 R₁(s). In some preferredembodiments of the present disclosure, in formula (G), R₁₃ is H,—N(R₁₇)(R₁₈), C₁₋₆ alkoxy, C₁₋₆ alkyl, or C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, or 5-7 membered heteroaryl, and R₁₇ and R₁₈are defined as above, wherein R₁₃ is optionally substituted with 1, 2, 3or 4 R₁(s). In some preferred embodiments of the present disclosure, informula (G), R₁₃ is —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, C₁₋₆ alkyl, or C₃₋₇cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 memberedheteroaryl, and R₁₇ and R₁₈ are defined as above, wherein R₁₃ isoptionally substituted with 1, 2, or 3 R₁(s). In some preferredembodiments of the present disclosure, in formula (G), R₁₃ is—N(R₁₇)(R₁₈), C₁₋₃ alkoxy, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl or C₁₋₄ alkyl, and R₁₇and R₁₈ are defined as above, wherein R₁₃ is optionally substituted with1, 2, or 3 R₁(s). In some preferred embodiments of the presentdisclosure, in formula (G), R₁₃ is —N(H)(C₁₋₃ alkyl), —N(H)(3-6 memberedcycloalkyl), —N(H) (4-6 membered heterocycloalkyl), —N(C₁₋₃ alkyl) (C₁₋₃alkyl), C₁₋₃ alkoxy, C3-6 cycloalkyl, 4-6 membered azacycloalkyl oroxacycloalkyl, phenyl, 5-6 membered azaaryl or C₁₋₄ alkyl; or R₁₃ is—N(R₁₇)(R₁₈), and R₁₇ and R₁₈ and the N atom connected thereto togetherform a 4-10 membered ring (where R₁₃ is optionally substituted with 1,2, or 3 R₁(s)). In some particularly preferred embodiments of thepresent disclosure, in formula (G), R₁₃ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy,propoxy, —N(H)(CH₃), —N(H)(CH₂CH₃), —N(H)(CH₂CH₂OH), —N(H) (CH₂CH₂CN),—N(CH₃)(CH₃), —N(H)(cyclopropyl), —N(H)(cyclobutyl),N(H)(tetrahydrofuranyl), pyrazinyl, pyridazinyl, pyrrolidinyl,pyrazolyl, piperidinyl, phenyl, azetidinyl, morpholinyl, piperazinyl ortetrahydropyranyl; or R₁₃ is —N(R₁₇)(R₁₈), and R₁₇ and R₁₈ and the Natom connected thereto together form a 7-membered ring (where R₁₃ isoptionally substituted with 1, 2, or 3 R₁(s)). In some particularlypreferred embodiments of the present disclosure, in formula (G), R₁₃ iscyclopropyl. In some particularly preferred embodiments of the presentdisclosure, in formula (G), R₁₃ is cyclobutyl. In some particularlypreferred embodiments of the present disclosure, in formula (G), R₁₃ iscyclopentyl. In some particularly preferred embodiments of the presentdisclosure, in formula (G), R₁₃ is cyclohexyl. In some particularlypreferred embodiments of the present disclosure, in formula (G), R₁₃ isa methyl group. In some particularly preferred embodiments of thepresent disclosure, in formula (G), R₁₃ is an ethyl group. In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁₃ is propyl. In some particularly preferred embodiments of thepresent disclosure, in formula (G), R₁₃ is a butyl group. In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁₃ is pyrazinyl. In some particularly preferred embodiments of thepresent disclosure, in formula (G), R₁₃ is a pyridazinyl. In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁₃ is a pyrrolidinyl. In some particularly preferred embodimentsof the present disclosure, in formula (G), R₁₃ is pyrazolyl. In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁₃ is piperidinyl. In some particularly preferred embodiments ofthe present disclosure, in formula (G), R₁₃ is phenyl. In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁₃ is azetidinyl. In some particularly preferred embodiments ofthe present disclosure, in formula (G), R₁₃ is morpholinyl. In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁₃ is piperazinyl. In some particularly preferred embodiments ofthe present disclosure, in formula (G), R₁₃ is tetrahydropyranyl. Insome particularly preferred embodiments of the present disclosure, informula (G), R₁₃ is methoxy. In some particularly preferred embodimentsof the present disclosure, in formula (G), R₁₃ is ethoxy. In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁₃ is —N(H)(CH₃). In some particularly preferred embodiments ofthe present disclosure, in formula (G), R₁₃ is —N(H)(CH₂CH₃). In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁₃ is —N(H)(CH₂CH₂OH). In some particularly preferred embodimentsof the present disclosure, in formula (G), R₁₃ is —N(H)(CH₂CH₂CN). Insome particularly preferred embodiments of the present disclosure, informula (G), R₁₃ is —N(CH₃)(CH₃). In some particularly preferredembodiments of the present disclosure, in formula (G), R₁₃ is —N(H)(cyclopropyl). In some particularly preferred embodiments of the presentdisclosure, in formula (G), R₁₃ is —N(H) (cyclobutyl). In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁₃ is —N(H) (tetrahydrofuranyl). In some particularly preferredembodiments of the present disclosure, in formula (G), R₁₃ is—N(R₁₇)(R₁₈), and R₁₇ and R₁₈ and the N atom connected to them togetherform a 7-membered ring.

In some particularly preferred embodiments of the present disclosure, informula (G), R₁₇ and R₁₈ are each independently selected from H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₅₋₇ aryl,and 5-7 membered heteroaryl, and are optionally substituted with one ormore of —OH, —CN, —SH, halogen, —NO₂, and SF₅. In some particularlypreferred embodiments of the present disclosure, in formula (G), R₁₇ andR₁₈ are each independently selected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,and C₃₋₇ heterocycloalkyl and are optionally substituted with one ormore of —OH, —CN, —SH, halogen, —NO₂, and SF₅. In some particularlypreferred embodiments of the present disclosure, in formula (G), R₁₇ andR₁₈ are each independently selected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,and C₃₋₇ heterocycloalkyl and are optionally substituted with one ormore of —OH and —CN. In some preferred embodiments of the presentdisclosure, in formula (G), R₁₇ and R₁₈ are each independently selectedfrom H, methyl, ethyl, propyl, 3-membered cycloalkyl, 4-memberedcycloalkyl, 5-membered cycloalkyl, 5-membered heterocycloalkyl, and6-membered heterocycloalkyl, and optionally substituted with one or moreof —OH and —CN. In some preferred embodiments of the present disclosure,in formula (G), R₁₇, R₁₈ and the N atom connected thereto together forma 4-10 membered ring. In some preferred embodiments of the presentdisclosure, in formula (G), R₁₇, R₁₈ and the N atom connected theretotogether form a 7-membered ring.

In some particularly preferred embodiments of the present disclosure, informula (G), L is C═O, and R₁₃ is —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —OH, —SH,—CN, halogen, —NO₂, —SF₅, or —S—C₁₋₄ alkyl, and R₁₃ is substituted with0, 1, 2, 3 or 4 R₁(s) in which R₁₇ and R₁₈ are each independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, C₅₋₇ aryl, and 5-7 membered heteroaryl, and areoptionally substituted with one or more of —OH, —CN, —SH, halogen,—NO₂,— and SF₅, or R₁₇, R₁₈ and the N atom connected thereto togetherform a 3-14 membered ring. In some particularly preferred embodiments ofthe present disclosure, in formula (G), L is C═O, and R₁₃ is—N(R₁₇)(R₁₈), or C₁₋₆ alkoxy, in which R₁₇ and R₁₈ are eachindependently selected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₃₋₇heterocycloalkyl and are optionally substituted with one or more of —OH,—CN, —SH, halogen, —NO₂,— and SF₅, or R₁₇, R₁₈ and the N atom connectedthereto together form a 3-10 membered ring. In some particularlypreferred embodiments of the present disclosure, in formula (G), L isC═O, and R₁₃ is methoxy, ethoxy, propoxy, —N(H)(CH₃), —N(H)(CH₂CH₃),—N(H)(CH₂CH₂OH), —N(H)(CH₂CH₂CN), —N(CH₃)(CH₃), —N(H)(cyclopropyl),—N(H) (cyclobutyl), —N(H) (tetrahydrofuranyl); or R₁₃ is —N(R₁₇)(R₁₈),and R₁₇, R₁₈ and the N atom connected thereto together form a 7-memberedring. In some particularly preferred embodiments of the presentdisclosure, in formula (G), L is C═O, and R₁₃ is methoxy. In someparticularly preferred embodiments of the present disclosure, in formula(G), L is C═O, and R₁₃ is ethoxy. In some particularly preferredembodiments of the present disclosure, in formula (G), L is C═O, and R₁₃is —N(H)(CH₃). In some particularly preferred embodiments of the presentdisclosure, in formula (G), L is C═O, and R₁₃ is —N(H)(CH₂CH₃). In someparticularly preferred embodiments of the present disclosure, in formula(G), L is C═O, and R₁₃ is —N(H)(CH₂CH₂OH). In some particularlypreferred embodiments of the present disclosure, in formula (G), L isC═O, and R₁₃ is —N(H)(CH₂CH₂CN). In some particularly preferredembodiments of the present disclosure, in formula (G), L is C═O, and R₁₃is —N(CH₃)(CH₃). In some particularly preferred embodiments of thepresent disclosure, in formula (G), L is C═O, and R₁₃ is—N(H)(cyclopropyl). In some particularly preferred embodiments of thepresent disclosure, in formula (G), L is C═O, and R₁₃ is—N(H)(cyclobutyl). In some particularly preferred embodiments of thepresent disclosure, in formula (G), L is C═O, and R₁₃ is—N(H)(tetrahydrofuranyl). In some particularly preferred embodiments ofthe present disclosure, in the formula (G), L is C═O, and R₁₃ is—N(R₁₇)(R₁₈), and R₁₇, R₁₈ and the N atom connected thereto togetherform a 7-membered ring.

In some particularly preferred embodiments of the present disclosure, informula (G), one, two or three R₂(s) are present and R₂ is selected fromH, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,and 4-10 membered heterocycloalkyl, in which the —S—C₁₋₄ alkyl, C₁₋₆alkyl, C₃₋₇ cycloalkyl, and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2 or 3 substituent(s) each independentlyselected from the group consisting of halogen, —OH, —NH₂, —NH(CH₃),—N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy. In some particularly preferred embodiments of the presentdisclosure, in formula (G), one, two or three R₂(s) are present and R₂is selected from halogen, C₁₋₆ alkyl and C₃₋₆ cycloalkyl, in which theC₁₋₆ alkyl and C₃₋₆ cycloalkyl are each optionally substituted with 1, 2or 3 substituent(s) each independently selected from the groupconsisting of halogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy. In some particularlypreferred embodiments of the present disclosure, in formula (G), one,two or three R₂(s) are present and R₂ is selected from halogen, and C₁₋₆alkyl, in which the C₁₋₆ alkyl is optionally substituted with 1, 2 or 3substituent(s) each independently selected from the group consisting ofhalogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy. In some particularly preferredembodiments of the present disclosure, in formula (G), one, or two R₂(s)are present and R₂ is selected from halogen, and C₁₋₆ alkyl. In someparticularly preferred embodiments of the present disclosure, in formula(G), one or two R₂(s) are present and R₂ is selected from fluorine,chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, andisobutyl. In some preferred embodiments of the present disclosure, informula (G), one or two R₂(s) are present, and R₂ is selected fromfluorine, chlorine, methyl, ethyl, n-propyl, and isopropyl. In somepreferred embodiments of the present disclosure, in formula (G), one ortwo R₂(s) are present, and R₂ is selected from fluorine, methyl, andethyl. In some preferred embodiments of the present disclosure, informula (G), one or two R₂ (s) are present, and R₂ is selected fromfluorine and ethyl. In some preferred embodiments of the presentdisclosure, in formula (G), one R₂ is present, and R₂ is selected fromfluorine and ethyl. In some preferred embodiments of the presentdisclosure, in formula (G), two R₂(s) are present, and R₂ is selectedfrom fluorine and ethyl. In some particularly preferred embodiments ofthe present disclosure, in formula (G), two R₂(s) are present which arerespectively fluorine and ethyl. In some particularly preferredembodiments of the present disclosure, in formula (G), one R₂ ispresent, and R₂ is an ethyl group.

In some preferred embodiments of the present disclosure, in formula (G),R₁₃ is substituted with 0, 1, 2, 3 or 4 R₁(s), and each R₁ isindependently selected from H, halogen, —OH, —NO₂, —CN, —SF₅, —SH,—S—C₁₋₄ alkyl, C₁₋₈ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, C₁₋₈ alkoxy, C₃₋₇cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclic heteroaryl,wherein the —S—C₁₋₄ alkyl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, andC₁₋₈ alkoxy are optionally substituted with 1, 2, 3, or 4 R₃(s), andwherein the C₃₋₇ cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl,5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclicheteroaryl are optionally substituted with 1, 2, 3 or 4 R₄(s). In somepreferred embodiments of the present disclosure, in formula (G), R₁₃ issubstituted with 0, 1, 2, 3 or 4 R₁(s), and each R₁ is independentlyselected from H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄ alkyl, C₁₋₈alkyl, C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, and5-7 membered heteroaryl, wherein the —S—C₁₋₄ alkyl, and C₁₋₈ alkyl areoptionally substituted with 1, 2, 3 or 4 R₃(s), and wherein the C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, and 5-7 memberedheteroaryl are optionally substituted with 1, 2, 3, or 4 R₄(s). In somepreferred embodiments of the present disclosure, in formula (G), R₁₃ issubstituted with 0, 1, 2, 3 or 4 R₁(s), and each R1 is independentlyselected from halogen, —OH, —CN, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, 3-7membered heterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, whereinthe C₁₋₈ alkyl is optionally substituted with 1, 2, 3 or 4 R₃(s), andwherein the C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl,5-7 membered heteroaryl are optionally substituted with 1, 2, 3 or 4R₄(s). In some preferred embodiments of the present disclosure, informula (G), R₁₃ is substituted with 0, 1, 2, 3 or 4 R₁(s), and each R₁is independently selected from halogen, —OH, —CN, C₁₋₈ alkyl, C₃₋₇cycloalkyl, and 3-7 membered heterocycloalkyl, wherein the C₁₋₈ alkyl isoptionally substituted with 1, 2, or 3 R₃(s), and wherein the C₃₋₇cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substitutedwith 1, 2, or 3 R₄(s). In some preferred embodiments of the presentdisclosure, in formula (G), R₁₃ is substituted with 0 or 1 R₁, and eachR₁ is independently selected from halogen, —OH, —CN, C₁₋₆ alkyl, C₃₋₇cycloalkyl, 5-7 membered heterocycloalkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 R₃(s), and wherein the C₃₋₇cycloalkyl, and 5-7-membered heterocycloalkyl are optionally substitutedwith 1, 2, or 3 R₄(s). In some preferred embodiments of the presentdisclosure, in formula (G), R₁₃ is substituted with 0 or 1 R₁, and eachR₁ is independently selected from halogen, —OH, —CN, C₁₋₄ alkyl, C₃₋₆cycloalkyl, and 5-7 membered heterocycloalkyl, wherein the C₁₋₄ alkyl isoptionally substituted with 1 or 2 R₃(s), and wherein the C₃₋₆cycloalkyl and 5-7 membered heterocycloalkyl are optionally substitutedwith 1, 2, or 3 R₄(s). In some particularly preferred embodiments of thepresent disclosure, in formula (G), R₁₃ is substituted with 0 or 1 R₁,and each R₁ is independently selected from methyl, ethyl, hydroxyl, —CN,piperidinyl, morpholinyl, piperazinyl, and cyclopropyl, wherein thepiperidinyl, morpholinyl, and piperazinyl are optionally substitutedwith 1, 2, 3 or 4 C₁₋₃ alkyl. In some particularly preferred embodimentsof the present disclosure, in formula (G), R₁₃ is substituted with 0 or1 R₁, and each R₁ is independently selected from methyl, ethyl, hydroxy,—CN, piperidinyl, morpholinyl, 1-methylpiperazinyl, and cyclopropyl. Insome particularly preferred embodiments of the present disclosure, informula (G), R₁ is absent. In some particularly preferred embodiments ofthe present disclosure, in formula (G), R₁ is 1-methylpiperazinyl. Insome particularly preferred embodiments of the present disclosure, informula (G), R₁ is methyl. In some particularly preferred embodiments ofthe present disclosure, in formula (G), R₁ is ethyl. In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁ is piperidinyl. In some particularly preferred embodiments ofthe present disclosure, in formula (G), R₁ is morpholinyl. In someparticularly preferred embodiments of the present disclosure, in formula(G), R₁ is hydroxyl. In some particularly preferred embodiments of thepresent disclosure, in formula (G), R₁ is —CN. In some particularlypreferred embodiments of the present disclosure, in formula (G), R₁ iscyclopropyl.

The preferred options of the respective substituents mentioned in theabove various preferred embodiments can be combined with each other inany way, and various combinations thereof are within the scope of thepresent disclosure. In the most preferred embodiments of the presentdisclosure, the compound of formula (G) is each specific compound shownin Example 1 to Example 58 herein. That is, the compound of formula (G)is selected from

-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinylpyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,    4H,6H)-yl)(1-methylpiperidin-4-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,    4H,6H)-yl)(5-(4-methylpiperzin-1-yl)pyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperzin-1-yl)pyrazin-2-yl)ketone;-   5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone;-   4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5    (1H,4H,6H)-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxylcyclobutyl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone;-   (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;-   5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one;-   (1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one);-   2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)ketone;-   Azetidin-1-yl((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperzin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperzin-1-yl)ketone;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;-   (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl) (3-hydroxylpyrrolidin-1-yl)ketone;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;-   (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl) (3-hydroxylpyrrolidin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylAzetidin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl)(4-hydroxylpiperidin-1-yl)ketone;-   2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide;-   2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide;-   2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)azetidine-3-nitrile;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidin-3-nitrile;-   2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   Methyl    2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-carboxylate;-   Ethyl    2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-carboxylate;-   (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;-   3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile;-   2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-carboxamide;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl)(2,6-diazaspiro[3.3]heptan-2-yl)ketone;-   (S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol;    and-   (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol.

In the compound of formula (G), when X₁, X₂, and X₃ are the same, thecompound of formula (G) can also be represented as a compound of formula(G′):

wherein X is N or CR₁₄, and R₁₄, R₁₃, R₁, L, and R₂ are as defined inthe compound of formula (G).

In a preferred embodiment, the present disclosure provides a compound ofFormula (G)′

or an isotopically labeled compound thereof, or an optical isomerthereof, a geometric isomer thereof, a tautomer thereof or a mixture ofvarious isomers, or a pharmaceutically acceptable salt thereof, or aprodrug thereof, or a metabolite thereof,wherein

X is N or CH;

L is C═O, O═S═O, CH₂ or a linkage; andR₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —SR₁₂, —OR₁₂, —CN, halogen, —NO₂,—SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl or C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclyl, C₅₋₁₁bicycloalkyl, or 5-11 membered bicyclic heteroalkyl, and R₁₃ issubstituted with 0, 1, 2, 3 or 4 R₁(s), in which R₁₇ and R₁₈ are eachindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₅₋₇aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 memberedbicyclic heteroaryl, 11-15 membered tricyclyl, C₅₋₁₁ bicycloalkyl, and5-11 membered bicyclic heteroalkyl and are optionally substituted withone or more substitutes each independently selected from —OH, —CN, —SH,halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, 7-11 membered bicyclic heteroaryl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂),—C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂,—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the—S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, C₅₋₇aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 memberedbicyclic heteroaryl are optionally substituted with 1, 2 or 3substitutes each independently selected from halogen, —CN, —OH, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl,—N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂,—C(═O)—N(R₉)(R₁₀), —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and—OR₁₂; or R₁₇, R₁₈ and the N atom connected thereto together form a 3-14membered ring; and0, 1, 2, 3 or 4 R₂(s) are present in formula (G′), and R₂ is selectedfrom H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄ alkyl, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl,—N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂,—C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂and —OR₁₂, in which the —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, and 7-11 membered bicyclic heteroaryl are each optionallysubstituted with 1, 2 or 3 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂; andR₁ is selected from H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄alkyl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₃₋₇cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl,11-15membered tricyclyl, C₅₋₁₁bicycloalkyl, 5-11 membered bicyclicheteroalkyl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀),—C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂),—S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the —S—C₁₋₄ alkyl, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, and C₁₋₈ alkoxy are optionallysubstituted with 1, 2, 3, or 4 R₃(s), and in which the C₃₋₇ cycloalkyl,3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl,C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclic heteroaryl areoptionally substituted with 1, 2, 3, or 4 R₄(s); andR₃ and R₄ are each independently selected from H, halogen, —OH, —NO₂,—CN, —SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclicheteroaryl, —N(R₅)(R₆), —N(R₁₁)(C(═O)R₁₂), —CON(R₇)(R₈), —C(═O)—R₁₂,—C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂and —OR₁₂, in which the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-10 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, and 7-11 membered bicyclic heteroaryl are each optionallysubstituted with 1, 2, 3 or 4 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₆ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂; andR₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ are each independently H orselected from the group consisting of C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₃₋₇cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein the substituents included inthe above group are each optionally substituted with 1, 2, 3 or 4substituent(s) each independently selected from the group consisting ofhalogen, —CF₃, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, oxo, C₁₋₄ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₄ hydroxyalkyl, —S—C₁₋₄alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄ alkyl, —C(═O)—NH₂,—C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy and C₁₋₄ haloalkoxy.

In some preferred embodiments of the present disclosure, an isotopicallylabeled compound of the above-mentioned compound of formula (G′) isprovided. In some more preferred embodiments of the present disclosure,an isotopically labeled compound of the compound of formula (G′) isprovided, wherein all Hs are each independently and optionallysubstituted with D.

In some preferred embodiments of the present disclosure, in formula(G′), X is N. In some more preferred embodiments of the presentdisclosure, in formula (G′), X is CH.

In some more preferred embodiments of the present disclosure, there isprovided an isotopically labeled compound of the compound of formula(G′), wherein all H are each independently and optionally substitutedwith D, and X is N. In some more preferred embodiments of the presentdisclosure, there is provided an isotopically labeled compound of thecompound of formula (G′), wherein all Hs are each independently andoptionally substituted with D, and X is CH.

In some preferred embodiments of the present disclosure, in formula(G′), L is C═O, O═S═O or CH₂. In some particularly preferred embodimentsof the present disclosure, in formula (G′), L is C═O. In someparticularly preferred embodiments of the present disclosure, in formula(G′), L is O ═S═O. In some particularly preferred embodiments of thepresent disclosure, in formula (G′), L is CH₂. In other embodiments ofthe present disclosure, in formula (G′), L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G′), X is CH, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G′), X is CH, and L is O ═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G′), X is CH, and L is CH2.

In some particularly preferred embodiments of the present disclosure, informula (G′), X is CH, and L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (G′), X is N, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (G′), X is N, and L is O ═S═O.

In some particularly preferred embodiments of the present disclosure, informula (G′), X is N, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (G′), X is N, and L is a linkage.

In some preferred embodiments of the present disclosure, in formula(G′), R₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —OH, —SH, —CN, halogen, —NO₂,—SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, or C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclyl,C₅₋₁₁bicycloalkyl, or 5-11 membered bicyclic heteroalkyl, in which R₁₇and R₁₈ are each independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₅₋₇ aryl, and 5-7 memberedheteroaryl, and are optionally substituted with one or more of —OH, —CN,—SH, halogen, —NO₂,— and SF₅, wherein R₁₃ is optionally substituted with1, 2, 3 or 4 R₁(s). In some preferred embodiments of the presentdisclosure, in formula (G′), R₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —OH,—SH, —CN, halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, or C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11membered bicyclic heteroaryl, or11-15 membered tricyclyl and R₁₇ and R₁₈ are defined as above, whereinR₁₃ is optionally substituted with 1, 2, 3 or 4 R₁(s). In some preferredembodiments of the present disclosure, in formula (G′), R₁₃ is H,—N(R₁₇)(R₁₈), C₁₋₆ alkoxy, C₁₋₆ alkyl, or C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, or 5-7 membered heteroaryl, and R₁₇ and R₁₈are defined as above, wherein R₁₃ is optionally substituted with 1, 2, 3or 4 R₁(s). In some preferred embodiments of the present disclosure, informula (G′), R₁₃ is —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, C₁₋₆ alkyl, or C₃₋₇cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 memberedheteroaryl, and R₁₇ and R₁₈ are defined as above, wherein R₁₃ isoptionally substituted with 1, 2, or 3 R₁(s). In some preferredembodiments of the present disclosure, in formula (G′), R₁₃ is—N(R₁₇)(R₁₈), C₁₋₃ alkoxy, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl or C₁₋₄ alkyl, and R₁₇and R₁₈ are defined as above, wherein R₁₃ is optionally substituted with1, 2, or 3 R₁(s). In some preferred embodiments of the presentdisclosure, in formula (G′), R₁₃ is —N(H)(C₁₋₃ alkyl), —N(H)(3-6membered cycloalkyl), —N(H) (4-6 membered heterocycloalkyl), —N(C₁₋₃alkyl) (C₁₋₃ alkyl), C₁₋₃ alkoxy, C3-6 cycloalkyl, 4-6 memberedazacycloalkyl or oxacycloalkyl, phenyl, 5-6 membered azaaryl or C₁₋₄alkyl; or R₁₃ is —N(R₁₇)(R₁₈), and R₁₇ and R₁₈ and the N atom connectedthereto together form a 4-10 membered ring (where R₁₃ is optionallysubstituted with 1, 2, or 3 R₁). In some particularly preferredembodiments of the present disclosure, in formula (G′), R₁₃ iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl,butyl, methoxy, ethoxy, propoxy, —N(H)(CH₃), —N(H)(CH₂CH₃),—N(H)(CH₂CH₂OH), —N(H) (CH₂CH₂CN), —N(CH₃)(CH₃), —N(H)(cyclopropyl),—N(H)(cyclobutyl), N(H)(tetrahydrofuranyl), pyrazinyl, pyridazinyl,pyrrolidinyl, pyrazolyl, piperidinyl, phenyl, azetidinyl, morpholinyl,piperazinyl or tetrahydropyranyl; or R₁₃ is —N(R₁₇)(R₁₈), and R₁₇ andR₁₈ and the N atom connected thereto together form a 7-membered ring(where R₁₃ is optionally substituted with 1, 2, or 3 R_(1s)). In someparticularly preferred embodiments of the present disclosure, in formula(G′), R₁₃ is cyclopropyl. In some particularly preferred embodiments ofthe present disclosure, in formula (G′), R₁₃ is cyclobutyl. In someparticularly preferred embodiments of the present disclosure, in formula(G′), R₁₃ is cyclopentyl. In some particularly preferred embodiments ofthe present disclosure, in formula (G′), R₁₃ is cyclohexyl. In someparticularly preferred embodiments of the present disclosure, in formula(G′), R₁₃ is a methyl group. In some particularly preferred embodimentsof the present disclosure, in formula (G′), R₁₃ is an ethyl group. Insome particularly preferred embodiments of the present disclosure, informula (G′), R₁₃ is propyl. In some particularly preferred embodimentsof the present disclosure, in formula (G′), R₁₃ is a butyl group. Insome particularly preferred embodiments of the present disclosure, informula (G′), R₁₃ is pyrazinyl. In some particularly preferredembodiments of the present disclosure, in formula (G′), R₁₃ is apyridazinyl. In some particularly preferred embodiments of the presentdisclosure, in formula (G′), R₁₃ is a pyrrolidinyl. In some particularlypreferred embodiments of the present disclosure, in formula (G′), R₁₃ ispyrazolyl. In some particularly preferred embodiments of the presentdisclosure, in formula (G′), R₁₃ is piperidinyl. In some particularlypreferred embodiments of the present disclosure, in formula (G′), R₁₃ isphenyl. In some particularly preferred embodiments of the presentdisclosure, in formula (G′), R₁₃ is azetidinyl. In some particularlypreferred embodiments of the present disclosure, in formula (G′), R₁₃ ismorpholinyl. In some particularly preferred embodiments of the presentdisclosure, in formula (G′), R₁₃ is piperazinyl. In some particularlypreferred embodiments of the present disclosure, in formula (G′), R₁₃ istetrahydropyranyl. In some particularly preferred embodiments of thepresent disclosure, in formula (G′), R₁₃ is methoxy. In someparticularly preferred embodiments of the present disclosure, in formula(G′), R₁₃ is ethoxy. In some particularly preferred embodiments of thepresent disclosure, in formula (G′), R₁₃ is —N(H)(CH₃). In someparticularly preferred embodiments of the present disclosure, in formula(G′), R₁₃ is —N(H)(CH₂CH₃). In some particularly preferred embodimentsof the present disclosure, in formula (G′), R₁₃ is —N(H)(CH₂CH₂OH). Insome particularly preferred embodiments of the present disclosure, informula (G′), R₁₃ is —N(H)(CH₂CH₂CN). In some particularly preferredembodiments of the present disclosure, in formula (G′), R₁₃ is—N(CH₃)(CH₃). In some particularly preferred embodiments of the presentdisclosure, in formula (G′), R₁₃ is —N(H) (cyclopropyl). In someparticularly preferred embodiments of the present disclosure, in formula(G′), R₁₃ is —N(H) (cyclobutyl). In some particularly preferredembodiments of the present disclosure, in formula (G′), R₁₃ is —N(H)(tetrahydrofuranyl). In some particularly preferred embodiments of thepresent disclosure, in formula (G′), R₁₃ is —N(R₁₇)(R₁₈), and R₁₇ andR₁₈ and the N atom connected to them together form a 7-membered ring.

In some particularly preferred embodiments of the present disclosure, informula (G′), R₁₇ and R₁₈ are each independently selected from H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₅₋₇ aryl,and 5-7 membered heteroaryl, and are optionally substituted with one ormore of —OH, —CN, —SH, halogen, —NO₂, and SF₅. In some particularlypreferred embodiments of the present disclosure, in formula (G′), R₁₇and R₁₈ are each independently selected from H, C₁₋₆ alkyl, C₃₋₇cycloalkyl, and C₃₋₇ heterocycloalkyl and are optionally substitutedwith one or more of —OH, —CN, —SH, halogen, —NO₂, and SF₅. In someparticularly preferred embodiments of the present disclosure, in formula(G′), R₁₇ and R₁₈ are each independently selected from H, C₁₋₆ alkyl,C₃₋₇ cycloalkyl, and C₃₋₇ heterocycloalkyl and are optionallysubstituted with one or more of —OH and —CN. In some preferredembodiments of the present disclosure, in formula (G′), R₁₇ and R₁₈ areeach independently selected from H, methyl, ethyl, propyl, 3-memberedcycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 5-memberedheterocycloalkyl, and 6-membered heterocycloalkyl, and optionallysubstituted with one or more of —OH and —CN. In some preferredembodiments of the present disclosure, in formula (G′), R₁₇, R₁₈ and theN atom connected thereto together form a 4-10 membered ring. In somepreferred embodiments of the present disclosure, in formula (G′), R₁₇,R₁₈ and the N atom connected thereto together form a 7-membered ring.

In some particularly preferred embodiments of the present disclosure, informula (G′), L is C═O, and R₁₃ is —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —OH, —SH,—CN, halogen, —NO₂, —SF₅, or —S—C₁₋₄ alkyl, and R₁₃ is substituted with0, 1, 2, 3 or 4 R₁(s) in which R₁₇ and R₁₈ are each independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, C₃₋₇heterocycloalkyl, C₅₋₇ aryl, and 5-7 membered heteroaryl, and areoptionally substituted with one or more of —OH, —CN, —SH, halogen,—NO₂,— and SF₅, or R₁₇, R₁₈ and the N atom connected thereto togetherform a 3-14 membered ring. In some particularly preferred embodiments ofthe present disclosure, in formula (G′), L is C═O, and R₁₃ is—N(R₁₇)(R₁₈), or C₁₋₆ alkoxy, in which R₁₇ and R₁₈ are eachindependently selected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₃₋₇heterocycloalkyl and are optionally substituted with one or more of —OH,—CN, —SH, halogen, —NO₂,— and SF₅, or R₁₇, R₁₈ and the N atom connectedthereto together form a 3-10 membered ring. In some particularlypreferred embodiments of the present disclosure, in formula (G′), L isC═O, and R₁₃ is methoxy, ethoxy, propoxy, —N(H)(CH₃), —N(H)(CH2CH₃),—N(H)(CH₂CH₂OH), —N(H)(CH₂CH₂CN), —N(CH₃)(CH₃), —N(H)(cyclopropyl),—N(H) (cyclobutyl), —N(H) (tetrahydrofuranyl); or R₁₃ is —N(R₁₇)(R₁₈),and R₁₇, R₁₈ and the N atom connected thereto together form a 7-memberedring. In some particularly preferred embodiments of the presentdisclosure, in formula (G′), L is C═O, and R₁₃ is methoxy. In someparticularly preferred embodiments of the present disclosure, in formula(G′), L is C═O, and R₁₃ is ethoxy. In some particularly preferredembodiments of the present disclosure, in formula (G′), L is C═O, andR₁₃ is —N(H)(CH₃). In some particularly preferred embodiments of thepresent disclosure, in formula (G′), L is C═O, and R₁₃ is —N(H)(CH₂CH₃).In some particularly preferred embodiments of the present disclosure, informula (G′), L is C═O, and R₁₃ is —N(H)(CH₂CH₂OH). In some particularlypreferred embodiments of the present disclosure, in formula (G′), L isC═O, and R₁₃ is —N(H)(CH₂CH₂CN). In some particularly preferredembodiments of the present disclosure, in formula (G′), L is C═O, andR₁₃ is —N(CH₃)(CH₃). In some particularly preferred embodiments of thepresent disclosure, in formula (G′), L is C═O, and R₁₃ is—N(H)(cyclopropyl). In some particularly preferred embodiments of thepresent disclosure, in formula (G′), L is C═O, and R₁₃ is—N(H)(cyclobutyl). In some particularly preferred embodiments of thepresent disclosure, in formula (G′), L is C═O, and R₁₃ is—N(H)(tetrahydrofuranyl). In some particularly preferred embodiments ofthe present disclosure, in the formula (G′), L is C═O, and R₁₃ is—N(R₁₇)(R₁₈), and R₁₇, R₁₈ and the N atom connected thereto togetherform a 7-membered ring.

In some particularly preferred embodiments of the present disclosure, informula (G′), one, two or three R₂(s) are present and R₂ is selectedfrom H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄ alkyl, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, and 4-10 membered heterocycloalkyl, in which the —S—C₁₋₄alkyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and 4-10 membered heterocycloalkylare each optionally substituted with 1, 2 or 3 substituent(s) eachindependently selected from the group consisting of halogen, —OH, —NH₂,—NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, andC₁₋₄ haloalkoxy. In some particularly preferred embodiments of thepresent disclosure, in formula (G′), one, two or three R₂(s) are presentand R₂ is selected from halogen, C₁₋₆ alkyl and C₃₋₆ cycloalkyl, inwhich the C₁₋₆ alkyl and C₃₋₆ cycloalkyl are each optionally substitutedwith 1, 2 or 3 substituent(s) each independently selected from the groupconsisting of halogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy. In some particularlypreferred embodiments of the present disclosure, in formula (G′), one,two or three R₂(s) are present and R₂ is selected from halogen, and C₁₋₆alkyl, in which the C₁₋₆ alkyl is optionally substituted with 1, 2 or 3substituent(s) each independently selected from the group consisting ofhalogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy. In some particularly preferredembodiments of the present disclosure, in formula (G′), 1, or two R₂(s)are present and R₂ is selected from halogen, and C₁₋₆ alkyl. In someparticularly preferred embodiments of the present disclosure, in formula(G′), one or two R₂(s) are present and R₂ is selected from fluorine,chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, andisobutyl. In some preferred embodiments of the present disclosure, informula (G′), one or two R₂(s) are present, and R₂ is selected fromfluorine, chlorine, methyl, ethyl, n-propyl, and isopropyl. In somepreferred embodiments of the present disclosure, in formula (G′), one ortwo R₂ (s) are present, and R₂ is selected from fluorine, methyl, andethyl. In some preferred embodiments of the present disclosure, informula (G′), one or two R₂(s) are present, and R₂ is selected fromfluorine and ethyl. In some preferred embodiments of the presentdisclosure, in formula (G′), one R₂ is present, and R₂ is selected fromfluorine and ethyl. In some preferred embodiments of the presentdisclosure, in formula (G′), two R₂(s) are present, and R₂ is selectedfrom fluorine and ethyl. In some particularly preferred embodiments ofthe present disclosure, in formula (G′), two R₂(s) are present which arerespectively fluorine and ethyl. In some particularly preferredembodiments of the present disclosure, in formula (G′), one R₂ ispresent, and R₂ is an ethyl group.

In some preferred embodiments of the present disclosure, in formula(G′), R₁₃ is substituted with 0, 1, 2, 3 or 4 R₁(s), and each R₁ isindependently selected from H, halogen, —OH, —NO₂, —CN, —SF₅, —SH,—S—C₁₋₄ alkyl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₃₋₇cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl,wherein the —S—C₁₋₄ alkyl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, andC₁₋₈ alkoxy are optionally substituted with 1, 2, 3, or 4 R₃(s), andwherein the C₃₋₇ cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl,5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclicheteroaryl are optionally substituted with 1, 2, 3 or 4 R₄(s). In somepreferred embodiments of the present disclosure, in formula (G′), R₁₃ issubstituted with 0, 1, 2, 3 or 4 R₁(s), and each R1 is independentlyselected from H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄ alkyl, C₁₋₈alkyl, C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7membered heteroaryl, wherein the —S—C₁₋₄ alkyl, and C₁₋₈ alkyl areoptionally substituted with 1, 2, 3 or 4 R₃(s), and wherein the C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, and 5-7 memberedheteroaryl are optionally substituted with 1, 2, 3, or 4 R₄(s). In somepreferred embodiments of the present disclosure, in formula (G′), R₁₃ issubstituted with 0, 1, 2, 3 or 4 R₁(s), and each R1 is independentlyselected from halogen, —OH, —CN, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, 3-7membered heterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, whereinthe C₁₋₈ alkyl is optionally substituted with 1, 2, 3 or 4 R₃(s), andwherein the C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl,5-7 membered heteroaryl are optionally substituted with 1, 2, 3 or 4R₄(s). In some preferred embodiments of the present disclosure, informula (G′), R₁₃ is substituted with 0, 1, 2, 3 or 4 R₁(s), and each R₁is independently selected from halogen, —OH, —CN, C₁₋₈ alkyl, C₃₋₇cycloalkyl, and 3-7 membered heterocycloalkyl, wherein the C₁₋₈ alkyl isoptionally substituted with 1, 2, or 3 R₃(s), and wherein the C₃₋₇cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substitutedwith 1, 2, or 3 R₄. In some preferred embodiments of the presentdisclosure, in formula (G′), R₁₃ is substituted with 0 or 1 R₁, and eachR1 is independently selected from halogen, —OH, —CN, C₁₋₆ alkyl, C₃₋₇cycloalkyl, 5-7 membered heterocycloalkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 R₃(s), and wherein the C₃₋₇cycloalkyl, and 5-7-membered heterocycloalkyl are optionally substitutedwith 1, 2, or 3 R₄(s). In some preferred embodiments of the presentdisclosure, in formula (G′), R₁₃ is substituted with 0 or 1 R₁, and eachR₁ is independently selected from halogen, —OH, —CN, C₁₋₄ alkyl, C₃₋₆cycloalkyl, and 5-7 membered heterocycloalkyl, wherein the C₁₋₄ alkyl isoptionally substituted with 1 or 2 R₃, and wherein the C₃₋₆ cycloalkyland 5-7 membered heterocycloalkyl are optionally substituted with 1, 2,or 3 R₄(s). In some particularly preferred embodiments of the presentdisclosure, in formula (G′), R₁₃ is substituted with 0 or 1 R₁, and eachR₁ is independently selected from methyl, ethyl, hydroxyl, —CN,piperidinyl, morpholinyl, piperazinyl, and cyclopropyl, wherein thepiperidinyl, morpholinyl, and piperazinyl are optionally substitutedwith 1, 2, 3 or 4 C₁₋₃ alkyl. In some particularly preferred embodimentsof the present disclosure, in formula (G′), R₁₃ is substituted with 0 or1 R₁, and each R₁ is independently selected from methyl, ethyl, hydroxy,—CN, piperidinyl, morpholinyl, 1-methylpiperazinyl, and cyclopropyl. Insome particularly preferred embodiments of the present disclosure, informula (G′), R₁ is absent. In some particularly preferred embodimentsof the present disclosure, in formula (G′), R₁ is 1-methylpiperazinyl.In some particularly preferred embodiments of the present disclosure, informula (G′), R₁ is methyl. In some particularly preferred embodimentsof the present disclosure, in formula (G′), R₁ is ethyl. In someparticularly preferred embodiments of the present disclosure, in formula(G′), R₁ is piperidinyl. In some particularly preferred embodiments ofthe present disclosure, in formula (G′), R₁ is morpholinyl. In someparticularly preferred embodiments of the present disclosure, in formula(G′), R₁ is hydroxyl. In some particularly preferred embodiments of thepresent disclosure, in formula (G′), R₁ is —CN. In some particularlypreferred embodiments of the present disclosure, in formula (G′), R₁ iscyclopropyl.

The preferred options of the respective substituents mentioned in theabove various preferred embodiments can be combined with each other inany way, and various combinations thereof are within the scope of thepresent disclosure.

In the compound of formula (G′), when R₁₃ is a ring, the compound offormula (G′) can also be represented as a compound of the followingformula (I):

wherein the ring A is C₃₋₇ cycloalkyl, ₃₋₇ membered heterocycloalkyl,C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 memberedbicyclic heteroaryl, 11-15 membered tricyclyl, C₅₋₁₁ bicyclic alkylgroup or 5-11 membered bicyclic heteroalkyl, which may be optionallysubstituted with R₁, and L, R₁, R₂, and X are defined as above in thecompound of formula (G′).

In particular, the present disclosure provides a compound of formula (I)as a JAK inhibitor:

or an isotopically labeled compound thereof, or an optical isomerthereof, a geometric isomer thereof, a tautomer thereof or a mixture ofvarious isomers, or a pharmaceutically acceptable salt thereof, or aprodrug thereof, or a metabolite thereof,in whichL is C═O, O═S═O, CH₂ or a linkage; and

X is CH or N;

The ring A is C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl,5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclicheteroaryl, or 11-15 membered tricyclyl;0, 1, 2, 3 or 4 R₁(s) are present in formula (I), and R₁ is selectedfrom H, halogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclic heteroaryl,in which the C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, and C₁₋₈ alkoxy areoptionally substituted with 1, 2, 3 or 4 R₃(s), and in which the C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl areoptionally substituted with 1, 2, 3 or 4 R₄(s),0, 1, 2, 3 or 4 R₂(s) are present in formula (I), and R₂ is selectedfrom H, halogen, —OH, —NO₂, —CN, —SF₅, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀),—C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂),—S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the C₁₋₆ alkyl, C₃₋₇cycloalkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2 or 3 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂;R₃ is selected from halogen, cyano, C₁₋₃ alkyl, hydroxy, C₁₋₆ alkoxy,—N(R₅)(R₆), —CON(R₇)(R₈) or 3-7 membered heterocycloalkyl, in which the3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or4 R₄(s);R₄ is selected from halogen, C₁₋₃ alkyl, hydroxyl, C₁₋₆ alkoxy, —NH₂,—NHCH₃ or —N(CH₃)₂;R₅, R₆, R₇, R₈ are each independently hydrogen or C₁₋₄ alkyl;R₉ is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₃₋₇ cycloalkyl;R₁₀ is H or selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein each substituent included inthe above group is optionally substituted with 1, 2, 3 or 4substituent(s) each independently selected from the group consisting of—OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄hydroxyalkyl, —S—C₁₋₄ alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxyand C₁₋₄haloalkoxy;R₁₁ is selected from H, C₁₋₄ alkyl and C₃₋₇ cycloalkyl; andR₁₂ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₇cycloalkyl, 4- to 14-membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein each substituent included inthe above group is optionally substituted with 1, 2 or 3 substituent(s)each independently selected from the group consisting of halogen, —CF₃,—CN, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, oxo, —S—C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy andC₁₋₄ haloalkoxy.

In some preferred embodiments of the present disclosure, in formula (I),L is C═O, O═S═O or CH₂. In some particularly preferred embodiments ofthe present disclosure, in formula (I), L is C═O. In some particularlypreferred embodiments of the present disclosure, in formula (I), L isO═S═O. In some particularly preferred embodiments of the presentdisclosure, in formula (I), L is CH₂. In other embodiments of thepresent disclosure, in formula (I), L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (I), X is CH. In other some embodiments of the presentdisclosure, in formula (I), X is N.

In some particularly preferred embodiments of the present disclosure, informula (I), X is CH, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (I), X is CH, and L is O═S═O.

In some particularly preferred embodiments of the present disclosure, informula (I), X is CH, and L is CH2.

In some particularly preferred embodiments of the present disclosure, informula (I), X is CH, and L is a linkage.

In some particularly preferred embodiments of the present disclosure, informula (I), X is N, and L is C═O.

In some particularly preferred embodiments of the present disclosure, informula (I), X is N, and L is O═S═O.

In some particularly preferred embodiments of the present disclosure, informula (I), X is N, and L is CH₂.

In some particularly preferred embodiments of the present disclosure, informula (I), X is N, and L is a linkage.

In some preferred embodiments of the present disclosure, in formula (I),the ring A is C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl,5-7 membered heteroaryl, where the ring A is optionally substituted with1, 2, 3 or 4 R₁(s). In some preferred embodiments of the presentdisclosure, in formula (I), the ring A is C₅₋₆ cycloalkyl, 5-6 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl wherein the ring A isoptionally substituted with 1, 2, 3 or 4 R₁(s). In some preferredembodiments of the present disclosure, in formula (I), the ring A is 5-6membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl wherein thering A is optionally substituted with 1, 2, 3 or 4 R₁(s). In somepreferred embodiments of the present disclosure, in formula (I), thering A is 5-6 membered azacycloalkyl, phenyl, 5-6 membered azaaryl,where the ring A is optionally substituted with 1, 2, 3 or 4 R₁(s). Insome preferred embodiments of the present disclosure, in formula (I),the ring A is pyrazinyl, pyrazolyl, piperidinyl or phenyl, where thering A is optionally substituted with 1, 2, 3 or 4 R₁(s). In someparticularly preferred embodiments of the present disclosure, in formula(I), the ring A is pyrazinyl. In some particularly preferred embodimentsof the present disclosure, in formula (I), the ring A is pyrazolyl. Insome particularly preferred embodiments of the present disclosure, informula (I), the ring A is piperidinyl. In some particularly preferredembodiments of the present disclosure, in formula (I), the ring A isphenyl.

In some preferred embodiments of the present disclosure, in formula (I),R₁ is absent or R₁ is selected from C₁₋₈ alkyl, C₂₋₅ alkenyl, C₂₋₅alkynyl, C₁₋₈ alkoxy, C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl,C₅₋₇ aryl, and 5-7 membered heteroaryl, wherein the C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, and C₁₋₈ alkoxy are optionally substituted with1, 2, 3 or 4 R(s)₃, and wherein the C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, and 5-7 membered heteroaryl group areoptionally substituted with 1, 2, 3, or 4 R₄(s). In some preferredembodiments of the present disclosure, in formula (I), R₁ is absent orR₁ is selected from Cn 8 alkyl, C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, wherein the C₁₋₈alkyl group is optionally substituted with 1, 2, 3 or 4 R₃(s), andwherein the C₃₋₇ cycloalkyl group, 3-7 membered heterocycloalkyl, C₅₋₇aryl, 5-7 membered heteroaryl are optionally substituted with 1, 2, 3,or 4 R₄(s). In some preferred embodiments of the present disclosure, informula (I), R₁ is absent or R₁ is selected from C₁₋₈ alkyl, and 3-7membered heterocycloalkyl, wherein the C₁₋₈ alkyl is optionallysubstituted with 1, 2, 3, or 4 R₃(s), and wherein the 3-7 memberedheterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R₄(s). Insome preferred embodiments of the present disclosure, in formula (I), R₁is absent or R₁ is selected from C₁₋₆ alkyl, 5-7 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl is optionally substituted with1, 2, 3, or 4 R₃(s), and wherein the 5-7 membered heterocycloalkyl isoptionally substituted with 1, 2, 3, or 4 R₄(s). In some preferredembodiments of the present disclosure, in formula (I), R₁ is absent orR₁ is selected from C₁₋₆ alkyl, 5-7 membered heterocycloalkyl, whereinthe C₁₋₆ alkyl is optionally substituted with 1 or 2 R₃, and wherein the5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or4 C₁₋₃ alkyl. In some preferred embodiments of the present disclosure,in formula (I), R₁ is absent or R₁ is selected from C₁₋₄ alkyl, and 5-7membered heterocycloalkyl, wherein the C₁₋₄ alkyl is optionallysubstituted with 1 or 2 R₃, and wherein the 5-7 memberedheterocycloalkyl is optionally substituted with 1, 2, 3 or 4 C₁₋₃ alkyl.In some preferred embodiments of the present disclosure, in formula (I),R₁ is absent or R₁ is selected from methyl, piperidinyl, morpholinyl,piperazinyl, wherein the piperidinyl, morpholinyl, and piperazinyl areoptionally substituted with 1, 2, 3 or 4 C₁₋₃ alkyl groups. In somepreferred embodiments of the present disclosure, in formula (I), R₁ isabsent or R₁ is selected from methyl, piperidinyl, morpholinyl, and1-methylpiperazinyl. In some particularly preferred embodiments of thepresent disclosure, in formula (I), R₁ is absent. In some particularlypreferred embodiments of the present disclosure, in formula (I), R₁ is1-methylpiperazinyl. In some particularly preferred embodiments of thepresent disclosure, in formula (I), R₁ is methyl. In some particularlypreferred embodiments of the present disclosure, in formula (I), R1 ispiperidinyl. In some particularly preferred embodiments of the presentdisclosure, in formula (I), R1 is morpholinyl.

In some particularly preferred embodiments of the present disclosure, informula (I), one, two or three R₂(s) are present and R₂ is selected fromhalogen, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl, in which the C₁₋₆ alkyl, andC₃₋₆ cycloalkyl are each optionally substituted with 1, 2 or 3substituent(s) each independently selected from the group consisting ofhalogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy. In some particularly preferredembodiments of the present disclosure, in formula (I), one, two or threeR₂(s) are present and R₂ is selected from halogen, and C₁₋₆ alkyl, inwhich the C₁₋₆ alkyl is optionally substituted with 1, 2 or 3substituent(s) each independently selected from the group consisting ofhalogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy. In some particularly preferredembodiments of the present disclosure, in formula (I), one or two R₂(s)are present and R₂ is selected from fluorine, chlorine, bromine, methyl,ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. In some preferredembodiments of the present disclosure, in formula (I), one or two R₂(s)are present, and R₂ is selected from fluorine, chlorine, methyl, ethyl,n-propyl, and isopropyl. In some preferred embodiments of the presentdisclosure, in formula (I), one or two R₂ (s) are present, and R₂ isselected from fluorine, methyl, and ethyl. In some preferred embodimentsof the present disclosure, in formula (I), one or two R₂ (s) arepresent, and R₂ is selected from fluorine and ethyl. In some preferredembodiments of the present disclosure, in formula (I), one R₂ ispresent, and R₂ is selected from fluorine and ethyl. In some preferredembodiments of the present disclosure, in formula (I), two R₂(s) arepresent, and R₂ is selected from fluorine and ethyl. In someparticularly preferred embodiments of the present disclosure, in formula(I), two R₂(s) are present which are respectively fluorine and ethyl. Insome particularly preferred embodiments of the present disclosure, informula (I), one R₂ is present, and R₂ is an ethyl group.

The preferred options of the respective substituents mentioned in theabove various preferred embodiments can be combined with each other inany way, and various combinations thereof are within the scope of thepresent disclosure.

In particular, the present disclosure provides a compound of formula (I)as a JAK inhibitor:

or an isotopically labeled compound thereof, or an optical isomerthereof, a geometric isomer thereof, a tautomer thereof or a mixture ofvarious isomers, or a pharmaceutically acceptable salt thereof, or aprodrug thereof, or a metabolite thereof,in which

L is C═O, and O═S═O; X is CH;

The ring A is 5-7 membered heteroaryl or C₅₋₇ aryl;0, 1, 2, 3 or 4 R₁(s) are present in formula (I), and R₁ is selectedfrom C₁₋₈ alkyl, and 3-7 membered heterocycloalkyl, in which the C₁₋₈alkyl is optionally substituted with 1, 2, 3 or 4 R₃(s), and in whichthe 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3or 4 R₄(s),1, 2, or 3 R₂(s) are present in formula (I), and R₂ is selected from H,halogen, —OH, —NO₂, —CN, —SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀),—C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂),—S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the C₁₋₆ alkyl, C₃₋₇cycloalkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2 or 3 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂;R₃ is selected from halogen, cyano, C₁₋₃ alkyl, hydroxy, C₁₋₆ alkoxy,—N(R₅)(R₆), —CON(R₇)(R₈) or 3-7 membered heterocycloalkyl, in which the3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or4 R₄(s);R₄ is selected from halogen, C₁₋₃ alkyl, hydroxyl, C₁₋₆ alkoxy, —NH₂,—NHCH₃ or —N(CH₃)₂;R₅, R₆, R₇, R₈ are each independently hydrogen or C₁₋₄ alkyl;R₉ is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₃₋₇ cycloalkyl;R₁₀ is H or selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein each substituent included inthe above group is optionally substituted with 1, 2, 3 or 4substituent(s) each independently selected from the group consisting of—OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄hydroxyalkyl, —S—C₁₋₄ alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxyand C₁₋₄haloalkoxy;R₁₁ is selected from H, C₁₋₄ alkyl and C₃₋₇ cycloalkyl; andR₁₂ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₇cycloalkyl, 4- to 14-membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein each substituent included inthe above group is optionally substituted with 1, 2 or 3 substituent(s)each independently selected from the group consisting of halogen, —CF₃,—CN, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, oxo, —S—C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy andC₁₋₄ haloalkoxy.

In some preferred embodiments of the present disclosure, in formula (I),L is O═S═O. In some preferred embodiments of the present disclosure, informula (I), L is C═O.

In some preferred embodiments of the present disclosure, in formula (I),the ring A is 5-6 membered heteroaryl or phenyl wherein the ring A isoptionally substituted with 1, 2, 3 or 4 R₁(s). In some preferredembodiments of the present disclosure, in formula (I), the ring A ispyrazinyl, pyrazolyl, or phenyl, where the ring A is optionallysubstituted with 1, 2, 3 or 4 R₁(s). In some particularly preferredembodiments of the present disclosure, in formula (I), the ring A ispyrazinyl. In some particularly preferred embodiments of the presentdisclosure, in formula (I), the ring A is phenyl.

In some preferred embodiments of the present disclosure, in formula (I),R₁ is absent or R₁ is selected from C₁₋₈ alkyl, and 3-7 memberedheterocycloalkyl, wherein the C1-8 alkyl is optionally substituted with1, 2, 3, or 4 R₃(s), and wherein the 3-7 membered heterocycloalkyl isoptionally substituted with 1, 2, 3, or 4 R₄(s). In some preferredembodiments of the present disclosure, in formula (I), R₁ is absent orR₁ is selected from Cn 6 alkyl, 5-7 membered heterocycloalkyl, whereinthe C₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 R₃(s), andwherein the 5-7 membered heterocycloalkyl is optionally substituted with1, 2, 3, or 4 R₄(s). In some preferred embodiments of the presentdisclosure, in formula (I), R₁ is absent or R₁ is selected from C₁₋₆alkyl, 5-7 membered heterocycloalkyl, wherein the C₁₋₆ alkyl isoptionally substituted with 1 or 2 R₃(s), and wherein the 5-7 memberedheterocycloalkyl is optionally substituted with 1, 2, 3 or 4 C₁₋₃ alkyl.In some preferred embodiments of the present disclosure, in formula (I),R₁ is absent or R₁ is selected from C₁₋₄ alkyl, and 5-7 memberedheterocycloalkyl, wherein the C₁₋₄ alkyl is optionally substituted with1 or 2 R₃, and wherein the 5-7 membered heterocycloalkyl is optionallysubstituted with 1, 2, 3 or 4 C₁₋₃ alkyl. In some preferred embodimentsof the present disclosure, in formula (I), R₁ is absent or R₁ isselected from methyl, piperidinyl, morpholinyl, wherein the piperidinyl,and morpholinyl are optionally substituted with 1, 2, 3 or 4 C₁₋₃ alkylgroups. In some preferred embodiments of the present disclosure, informula (I), R₁ is absent or R₁ is selected from methyl, piperidinyl,and morpholinyl. In some particularly preferred embodiments of thepresent disclosure, in formula (I), R₁ is absent. In some particularlypreferred embodiments of the present disclosure, in formula (I), R₁ ismethyl. In some particularly preferred embodiments of the presentdisclosure, in formula (I), R1 is piperidinyl. In some particularlypreferred embodiments of the present disclosure, in formula (I), R1 ismorpholinyl.

In some particularly preferred embodiments of the present disclosure, informula (I), one or two R₂(s) are present and R₂ is selected fromhalogen, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl, in which the C₁₋₆ alkyl, andC₃₋₆ cycloalkyl are each optionally substituted with 1, 2 or 3substituent(s) each independently selected from the group consisting ofhalogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy. In some particularly preferredembodiments of the present disclosure, in formula (I), one, or two R₂(s)are present and R₂ is selected from halogen, and C₁₋₆ alkyl, in whichthe C₁₋₆ alkyl is optionally substituted with 1, 2 or 3 substituent(s)each independently selected from the group consisting of halogen, —OH,—NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,and C₁₋₄ haloalkoxy. In some particularly preferred embodiments of thepresent disclosure, in formula (I), two R₂s are present and R₂ isselected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl,isopropyl, n-butyl, and isobutyl. In some preferred embodiments of thepresent disclosure, in formula (I), two R₂s are present, and R₂ isselected from fluorine, chlorine, methyl, ethyl, n-propyl, andisopropyl. In some preferred embodiments of the present disclosure, informula (I), two R₂s are present, and R₂ is selected from fluorine,methyl, and ethyl. In some preferred embodiments of the presentdisclosure, in formula (I), two R₂s are present, and R₂ is selected fromfluorine and ethyl. In some preferred embodiments of the presentdisclosure, in formula (I), two R₂(s) are present, and R₂ is selectedfrom fluorine and ethyl. In some particularly preferred embodiments ofthe present disclosure, in formula (I), two R₂(s) are present which arerespectively fluorine and ethyl.

The preferred options of the respective substituents mentioned in theabove various preferred embodiments can be combined with each other inany way, and various combinations thereof are within the scope of thepresent disclosure.

In a more preferred embodiment of the present disclosure, the compoundof formula (I) is selected from

-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinylpyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,    4H,6H)-yl)(1-methylpiperidin-4-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperzin-1-yl)pyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperzin-1-yl)pyrazin-2-yl)ketone;-   5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   Cyclopropyl    (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5    (1H,4H,6H)-yl)ketone;-   4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   Cyclobutyl    (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5    (1H,4H,6H)-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone;-   4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)ketone;-   Azetidin-1-yl    ((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperzin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperzin-1-yl)ketone;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;-   (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl) (3-hydroxylpyrrolidin-1-yl)ketone;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;-   (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl) (3-hydroxylpyrrolidin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylAzetidin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl)(4-hydroxylpiperidin-1-yl)ketone;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)azetidine-3-nitrile;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidin-3-nitrile;-   (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;-   (S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol;    and-   (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol.

In some of the most preferred embodiments of the present disclosure, thecompound of formula (I) is each specific compound shown in Example 1 toExample 8 herein. That is, the compound of formula (I) is selected from

-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinpyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone;-   5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidin-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol;-   5-ethyl-2-fluoro-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol;-   3-ethyl-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol;-   5-ethyl-2-fluoro-4-(3-(5-(bemzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;    and-   5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol.

For simplicity, hereinafter, the term “a compound as shown by Formula(G)” or “a compound of Formula (G)” or “a compound of the invention” or“a compound according to the invention” also encompasses any opticalisomer, geometric isomer, tautomer or a mixture of various isomers ofthe compound of Formula (G); the term “a compound as shown by Formula(G′)” or “a compound of Formula (G′)” or “a compound of the invention”or “a compound according to the invention” also encompasses any opticalisomer, geometric isomer, tautomer or a mixture of various isomers ofthe compound of Formula (G′); and the term “a compound as shown byFormula (I)” or “a compound of Formula (I)” or “a compound of theinvention” or “a compound according to the invention” also encompassesany optical isomer, geometric isomer, tautomer or a mixture of variousisomers of the compound of Formula (I).

The term “optical isomer” refers that when a compound has one or morechiral centers, each chiral center may have an R configuration or an Sconfiguration, and the various isomers thus constituted are known as anoptical isomer. Optical isomers comprise all diastereomers, enantiomers,meso forms, racemates or mixtures thereof. For example, optical isomerscan be separated by a chiral chromatography or by chiral synthesis.

The term “geometric isomer” refers that when a double bond is present ina compound, the compound may exist as a cis isomer, a trans isomer, an Eisomer, or a Z isomer. A geometric isomer comprises a cis isomer, transisomer, E isomer, Z isomer, or a mixture thereof.

The term “tautomer” refers to an isomer that is formed by rapid movementof an atom at two positions in a single molecule. It will be understoodby those skilled in the art that tautomers can be mutually transformed,and in a certain state, may coexist by reaching an equilibrium state. Asused herein, the term “a compound as shown by Formula (G)” alsoencompasses any tautomer of the compound of Formula (G); “a compound asshown by Formula (G′)” also encompasses any tautomer of the compound ofFormula (G′); and “a compound as shown by Formula (I)” also encompassesany tautomer of the compound of Formula (I).

Unless otherwise indicated, reference to “a compound as shown by Formula(G)” or “a compound of Formula (G)” or “a compound of the invention” or“a compound according to the invention” herein also encompassesisotopically-labeled compounds obtained by replacing any atom of thecompound with its isotopic atom; reference to “a compound as shown byFormula (G′)” or “a compound of Formula (G′)” or “a compound of theinvention” or “a compound according to the invention” herein alsoencompasses isotopically-labeled compounds obtained by replacing anyatom of the compound with its isotopic atom; and reference to “acompound as shown by Formula (I)” or “a compound of Formula (I)” or “acompound of the invention” or “a compound according to the invention”herein also encompasses isotopically-labeled compounds obtained byreplacing any atom of the compound with its isotopic atom.

The invention comprises all pharmaceutically acceptableisotopically-labeled compounds of Formula (G) wherein one or more atomsare replaced by atoms having the same atomic number but different atomicmass or mass number than those normally found in nature. The inventioncomprises all pharmaceutically acceptable isotopically-labeled compoundsof Formula (G′) wherein one or more atoms are replaced by atoms havingthe same atomic number but different atomic mass or mass number thanthose normally found in nature. The invention comprises allpharmaceutically acceptable isotopically-labeled compounds of Formula(I) wherein one or more atoms are replaced by atoms having the sameatomic number but different atomic mass or mass number than thosenormally found in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H (D) and ³H (T), ofcarbon, such as ¹¹C, ¹³C and ¹⁴C, of chlorine, such as ³⁶Cl, offluorine, such as ¹⁸F, of iodine, such as ¹²³I and ¹²⁵I, of nitrogen,such as ¹³N and ¹⁵N, of oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, and ofsulphur, such as ³⁵S.

Certain isotopically-labelled compounds of formula (G), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. Certain isotopically-labelledcompounds of formula (G′), for example, those incorporating aradioactive isotope, are useful in drug and/or substrate tissuedistribution studies. Certain isotopically-labelled compounds of formula(I), for example, those incorporating a radioactive isotope, are usefulin drug and/or substrate tissue distribution studies. The radioactiveisotopes deuterium, i.e. ²H, and carbon-14, i.e. ¹⁴C, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of formula (G) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed. Isotopically-labeledcompounds of formula (G′) can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying Examples and Preparations usingan appropriate isotopically-labeled reagents in place of the non-labeledreagent previously employed. Isotopically-labeled compounds of formula(I) can generally be prepared by conventional techniques known to thoseskilled in the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

The compound of formula (G) may exist in the form of a pharmaceuticallyacceptable salt, for example, an acid addition salt and/or a baseaddition salt of the compound of formula (G). Unless otherwiseindicated, “a pharmaceutically acceptable salt” as used herein includesacid addition salts or base addition salts that may appear in thecompound of formula (G). The compound of formula (G′) may exist in theform of a pharmaceutically acceptable salt, for example, an acidaddition salt and/or a base addition salt of the compound of formula(G′). Unless otherwise indicated, “a pharmaceutically acceptable salt”as used herein includes acid addition salts or base addition salts thatmay appear in the compound of formula (G′). The compound of formula (I)may exist in the form of a pharmaceutically acceptable salt, forexample, an acid addition salt and/or a base addition salt of thecompound of formula (I). Unless otherwise indicated, “a pharmaceuticallyacceptable salt” as used herein includes acid addition salts or baseaddition salts that may appear in the compound of formula (I).

The pharmaceutically acceptable salt of the compound of formula (G), thecompound of formula (G′) and the compound of formula (I) include acidaddition salts and base addition salts thereof. Suitable acid additionsalts are formed from acids that form non-toxic salts. Examples includebut are not limited to: acetate, adipate, aspartate, benzoate,benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate,camphor sulfonate, citrate, cyclohexamine sulfonate, ethanedisulfonate,formate, fumarate, glucoheptonate, gluconate, glucuronate,hexafluorophosphate, 2-(4-hydroxybenzyl) benzoate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,2-isethionate, lactate, malate, maleate, malonate, methanesulfonate,methyl sulfate, naphthalate, 2-naphthalenesulfonate, nicotinate,nitrate, orotate, oxalate, palmitate, phosphate/hydrogenphosphate/dihydrogen phosphate, pyroglutamate, glucarate, stearate,salicylate, tannate, tartrate, tosylate and trifluoroacetate. Suitablebase addition salts are formed from bases that form non-toxic salts.Examples thereof include, but are not limited to: aluminum, arginine,calcium, choline, diethylamine, diethanolamine, glycine, lysine,magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, andzinc salts. It is also possible to form half salts of acids and bases,such as hemisulfate and hemicalcium salts. For a review of suitablesalts, please refer to Handbook of Pharmaceutical Salts: Properties,Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods forpreparing pharmaceutically acceptable salts of the compounds describedherein are known to those skilled in the art.

Certain compounds of the invention may exist in unsolvated form as wellas solvated forms, including hydrated forms. In general, the compoundsof formula (G), the compounds of formula (G′) and the compounds offormula (I), whether present in solvated form or in unsolvated form, areincluded within the scope of the invention.

Certain compounds of the invention may exist in different crystalline oramorphous forms, and the compounds of formula (G), the compounds offormula (G′) and the compounds of Formula (I) present in any forms, areincluded within the scope of the invention.

To avoid ambiguity, the definitions of some terms used herein are givenbelow. Unless otherwise stated, the meanings of the terms used hereinare as follows.

The term “pharmaceutically acceptable” means that the correspondingcompound, carrier or molecule is suitable for administration to humans.Preferably, the term refers to it is approved by regulatory agenciessuch as CFDA (China), EMEA (Europe), FDA (United States), and othernational regulatory agencies to be suitable for mammals, preferablyhumans.

The “prodrug” refers to a derivative that is converted into a compoundof the present disclosure by a reaction with enzymes, gastric acid, andthe like in the living body under physiological conditions, for example,through oxidation, reduction, hydrolysis, and the like catalyzed byenzymes.

The “metabolite” refers to all molecules derived from any compound ofthe present disclosure in a cell or organism, preferably a human.

The term “hydroxy” refers to —OH.

The term “halogen” or “halo” refers to —F, —Cl, —Br, or —I.

The term “cyano” refers to —CN.

In the present disclosure, when there are multiple substituents of acertain type, each substituent is independently selected from eachother, and these substituents may be the same or different. For example,when there are 2, 3, or 4 R₁s, these R₁s may be the same or different.For example, when there are 2, 3, or 4 R₂s, these R₂s may be the same ordifferent. For example, when R₁ and R₂ are both —N(R₉)(R₁₀), Ry and R₁₀contained in R₁ and R₂ can be independently selected, that is, R₉ in R₁and R₉ in R₂ can be the same or different, and R₁₀ in R₁ and R₁₀ in R₂may be the same or different. For example, when there are two R₁s, andthe two R₁s are both —N(R₉)(R₁₀), R₉ and R₁₀ in the two R₁s can beselected independently, that is, R₉ in the first R₁ and R₉ in the secondR₁ may be the same or different, and R₁₀ in the first R₁ and R₁₀ in thesecond R₁ may be the same or different. The above statement applies toR₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R₁₇, R₁₈.

As used herein, the term “substituted” means that one or more(preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in a groupare independently replaced by a corresponding number of substituents.

As used herein, the term “independently” means that when the number ofsubstituents is more than one, these substituents may be the same ordifferent.

As used herein, the term “optional” or “optionally” means that the eventdescribed therein may or may not occur. For example, an “optionallysubstituted” group means that the group may be unsubstituted orsubstituted.

As used herein, the term “heteroatom” as used herein refers to oxygen(O), nitrogen (N), or S(O)_(m) in which m may be 0, 1 or 2, i.e. asulfur atom S, or a sulfoxide group SO, or a sulfonyl group S(O)₂).

As used herein, the term “alkyl” refers to saturated aliphatichydrocarbons, including straight and branched chains. In someembodiments, the alkyl group has 1-8, or 1-6, or 1-3 carbon atoms. Forexample, the term “C₁₋₈ alkyl” refers to a straight or branched chaingroup of atoms having 1-8 carbon atoms. The term “C₁₋₈ alkyl” includesthe terms “Cn 6 alkyl”, “C₁-C₃ alkyl” and “C₁-C₄ alkyl” in itsdefinition. Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl,(R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl,2,3-dimethylbutyl, hexyl, and the like. The alkyl group may beoptionally substituted with one or more (for example, 1 to 5) suitablesubstituent(s).

As used herein, the term “alkenyl” refers to an aliphatic hydrocarbonhaving at least one carbon-carbon double bond, including straight andbranched chains having at least one carbon-carbon double bond. In someembodiments, alkenyl groups have 2-8 carbon atoms, 2-6 carbon atoms, 3-6carbon atoms, or 2-4 carbon atoms. For example, the term “C₂₋₈ alkenyl”refers to a linear or branched unsaturated atomic group (having at leastone carbon-carbon double bond) having 2-8 carbon atoms. The double bondmay or may not be the point of attachment of another group. Alkenylgroups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl,2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, and the like. Alkenylgroups may be optionally substituted with one or more (for example, 1 to5) suitable substituent(s). When the compound of formula (I) contains analkenyl group, the alkenyl group may be present in the pure E form, thepure Z form, or any mixture thereof.

As used herein, the term “alkynyl” refers to an aliphatic hydrocarbonhaving at least one carbon-carbon triple bond, including straight andbranched chains having at least one carbon-carbon triple bond. In someembodiments, an alkynyl group has 2-8 carbon atoms, 2-6 carbon atoms,3-6 carbon atoms, or 2-4 carbon atoms. For example, the term “C₂₋₈alkynyl” refers to a linear or branched unsaturated atomic group (havingat least one carbon-carbon triple bond) having 2-8 carbon atoms. Thetriple bond may or may not be the point of attachment of another group.Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl,2-propynyl, 2-methyl-2-propynyl, butynyl, pentynyl, 3-hexynyl, and thelike. The alkynyl group may be optionally substituted with one or more(for example, 1 to 5) suitable substituent(s).

As used herein, the term “C₃₋₇ cycloalkyl” refers to a cycloalkyl grouphaving 3-7 carbon atoms forming a ring, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. The cycloalkyl maybe optionally substituted with one or more suitable substituent(s).

As used herein, the term “n-membered heterocycloalkyl” refers to acycloalkyl group having m ring-forming carbon atoms and (n-m)ring-forming heteroatoms, the heteroatoms being selected from O, S andN. For example, 3-7 membered heterocycloalkyl includes, but not limitedto, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine,morpholine, piperazine, oxepane, thiepane, and azepine. Theheterocycloalkyl may be optionally substituted with one or more suitablesubstituent(s).

As used herein, the term “C₅₋₇ aryl” refers to an aryl group having anaromatic ring containing 5-7 carbon atoms, preferably phenyl.

As used herein, the term “n-membered heteroaryl” refers to a heteroarylgroup having m carbon atoms forming an aromatic ring and (n-m)heteroatoms forming an aromatic ring, the heteroatoms being selectedfrom O, S and N. For example, 5-7 membered heteroaryl includes but notlimited to pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, andpyridine. The heteroaryl may be optionally substituted with one or moresuitable substituent(s).

As used herein, the term “C₇₋₁₁ bicyclic aryl” refers to a bicyclic arylgroup having 7-11 carbon atoms, such as naphthalene, indene and thelike. The bicyclic aryl may be optionally substituted with one or moresuitable substituent(s).

As used herein, the term “n-membered bicyclic heteroaryl” refers to abicyclic heteroaryl group having m carbon atoms forming an aromaticbicyclic ring and (n-m) heteroatoms forming an aromatic bicyclic ring,and the heteroatoms are selected from O, S and N. For example, 7-11membered bicyclic heteroaryl includes, but not limited to, quinoline,isoquinoline, benzothiazole, and the like. The bicyclic heteroaryl maybe optionally substituted with one or more suitable substituent(s).

As used herein, the term “11-15 membered tricyclyl” includes but notlimited to acridine and the like. The 11-15 membered tricyclyl may beoptionally substituted with one or more suitable substituent(s).

As used herein, the term “haloalkyl” refers to an alkyl group having oneor more halogen substituent(s) (up to perhaloalkyl, that is, eachhydrogen atom of the alkyl is replaced by a halogen atom). For example,the term “C₁₋₆ haloalkyl” refers to a C₁₋₆ alkyl group with one or morehalogen substituent(s) (up to perhaloalkyl, that is, each hydrogen atomof the alkyl group is replaced by a halogen atom). As another example,the term “C₁₋₄ haloalkyl” refers to a C₁₋₄ alkyl group with one or morehalogen substituent(s) (up to perhaloalkyl, that is, each hydrogen atomof the alkyl group is replaced by a halogen atom); the term “C₁₋₃haloalkyl” refers to a C₁₋₃ alkyl group with one or more halogensubstituent(s) (up to perhaloalkyl, that is, each hydrogen atom of thealkyl group is replaced by a halogen atom); and the term “C₁₋₂haloalkyl” refers to a C₁₋₂ alkyl group (i.e. methyl or ethyl) with oneor more halogen substituent(s) (up to perhaloalkyl, that is, eachhydrogen atom of the alkyl group is replaced by a halogen atom). Asanother example, the term “C₁ haloalkyl” refers to a methyl group with1, 2, or 3 halogen substituent(s). Examples of haloalkyl groups include:CF₃, C₂F₅, CHF₂, CH₂F, CH₂CF₃, CH₂Cl, and the like.

As used herein, the term “alkoxy” refers to alkyl with a single bondattached to an oxygen atom. The point of attachment of the alkoxy groupto a molecule is through the oxygen atom. Alkoxy can be described asalkyl-O—. The term “C₁₋₆ alkoxy” refers to a linear or branched alkoxygroup containing 1 to 6 carbon atoms. The term “C₁₋₆ alkoxy” includesthe term “C₁₋₃ alkoxy” in its definition. Alkoxy includes, but notlimited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexoxy, andthe like. The alkoxy group may be optionally substituted with one ormore suitable substituent(s).

Herein, a numerical range relating to the number of substituents, thenumber of carbon atoms, or the number of ring members represents anenumeration of all integers in the range, and the range is only asimplified representation thereof. For example:

“1-4 substituent(s)” means 1, 2, 3 or 4 substituent(s);“1-3 substituent(s)” means a 1, 2 or 3 substituent(s);“3 to 12-membered ring” means a 3, 4, 5, 6, 7, 8, 9, 10, 11 or12-membered ring;“3 to 14-membered ring” means a 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or14-membered ring;“3 to 8 membered ring” means a 3, 4, 5, 6, 7, or 8 membered ring;“1-12 carbon atoms” or “C₁₋₁₂” means 1 (Ct), 2 (C₂), 3 (C₃), 4 (C₄), 5(C₅), 6 (C₆), 7 (C₇), 8 (C₈), 9 (C₉), 10 (C₁₀), 11 (Cn) or 12 (C₁₂)carbon atoms;“1-6 carbon atoms” or “C₁₋₆” means 1 (Ct), 2 (C₂), 3 (C₃), 4 (C₄), 5(C₅) or 6 (C₆) carbon atoms;“1-4 carbon atoms” or “C₁₋₄” means 1 (C₁), 2 (C₂), 3 (C₃), 4 (C₄) carbonatoms;“2-6 carbon atoms” or “C₂₋₆” means 2 (C₂), 3 (C₃), 4 (C₄), 5 (C₅) or 6(C₆) carbon atoms;“C₃₋₈” means 3 (C₃), 4 (C₄), 5 (C₅), 6 (C₆), 7 (C₇), 8 (C₈) carbonatoms; and“3 to 8 ring members” means 3, 4, 5, 6, 7, or 8 ring members.

Thus, a numerical range associated with the number of substituents, thenumber of carbon atoms, or the number of ring members also encompassesany one of its subranges, and each subrange is also considered to bedisclosed herein.

In a second aspect, the present disclosure provides a pharmaceuticalcomposition comprising the above mentioned compounds, or an isotopicallylabeled compound thereof, or an optical isomer thereof, a geometricisomer thereof, a tautomer thereof or a mixture of various isomers, or apharmaceutically acceptable salt thereof, or a prodrug thereof, or ametabolite thereof, and one or more pharmaceutically acceptablecarriers, adjuvants or excipients.

The pharmaceutical compositions of the invention may be formulated assuitable dosage forms for oral, external (including not limited toexternal application, spraying, and the like), parenteral (includingsubcutaneous, intramuscular, intradermal and intravenous), bronchial ornasal administration as desire. Preferably, the pharmaceuticalcompositions of the invention may be formulated as suitable dosage formsfor oral or external administration. More preferably, the pharmaceuticalcompositions of the invention may be formulated as suitable dosage formsfor oral administration.

If a solid carrier is used, the preparation may be tableted, placed in ahard gelatin capsule in powder or pellet form, or in the form of atroche or lozenge. The solid carrier may contain conventional excipientssuch as binding agents, fillers, tableting lubricants, disintegrants,wetting agents and the like. The tablet may, if desired, be film coatedby conventional techniques. If a liquid carrier is employed, thepreparation may be in the form of a syrup, emulsion, paste, soft gelatincapsule, sterile vehicle for injection, an aqueous or non-aqueous liquidsuspension, or may be a dry product for reconstitution with water orother suitable vehicle before use. Liquid preparations may containconventional additives such as suspending agents, emulsifying agents,wetting agents, non-aqueous vehicle (including edible oils),preservatives, as well as flavoring and/or coloring agents. Forparenteral administration, a vehicle normally will comprise sterilewater, at least in large part, although saline solutions, glucosesolutions and like may be utilized. Injectable suspensions also may beused, in which case conventional suspending agents may be employed.Conventional preservatives, buffering agents and the like also may beadded to the parenteral dosage forms. The pharmaceutical compositionsare prepared by conventional techniques appropriate to the desiredpreparation containing appropriate amounts of the active ingredient,that is, the compound of Formula (G), the compound of Formula (G′) orthe compound of Formula (I) according to the invention.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate.

These compositions may also contain excipients such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate; (e) solution retarders, as for example paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite; and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethyleneglycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylatedisostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Dosage forms for topical administration of a compound of the inventioninclude paste, powders, sprays, and inhalants. The active component isadmixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The external dosage form of the compound of the present disclosure maybe in the form of a water-in-oil (W/O) or oil-in-water (O/W) emulsion, amulti-emulsion form, such as a water-in-oil-in-water (W/O/W) form or anoil-in-water-oil (O/W/O) emulsion, or in the form of water dispersion orlipid dispersion, gel or aerosol.

The external dosage form of the compound of the present disclosure maycontain additives and aids, such as emulsifiers, thickeners, gellingagents, water fixatives, spreading agents, stabilizers, dyes,fragrances, and preservatives. Suitable emulsifiers include stearicacid, triethanolamine and PEG-40-stearate. Suitable thickeners includeglyceryl monostearate and PEG600. Suitable preservatives include propylparaben and chlorocresol. Suitable spreading agents include dimethiconeand polydimethylcyclosiloxane. Suitable water fixatives includepolyethylene glycol, preferably polyethylene glycol 600.

The external dosage form of the compound of the present disclosure mayinclude pastes, lotions, gels, emulsions, microemulsions, sprays, skinpatches, and the like, which can be applied topically to treat atopicdermatitis, eczema, psoriasis, and scleroderma, itching, vitiligo, hairloss and other skin diseases. In particular, the external dosage form ofthe compound of the present disclosure is pastes, which can be appliedtopically to treat skin diseases such as atopic dermatitis, eczema,psoriasis, scleroderma, itching, vitiligo, and hair loss and other skindiseases.

The amount of the compound of formula (G), the compound of formula (G′)or the compound of formula (I) in the pharmaceutical composition anddosage form can be appropriately determined by those skilled in the artas needed. For example, the compound of formula (G), the compound offormula (G′) or the compound of formula (I) can be present in thepharmaceutical composition or dosage form in a therapeutically effectiveamount.

In a third aspect, the present disclosure provides use of the compoundas described above, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof, or thecomposition as described above in the preparation of a medicament forthe treatment and/or prevention of JAK-related diseases or disorders.

“Diseases or disorders related to JAK” include but not limited to:

Arthritis, including rheumatoid arthritis, juvenile arthritis andpsoriatic arthritis; Autoimmune diseases or disorders, including singleorgan or single cell type autoimmune disorders, such as Hashimoto'sthyroiditis, autoimmune hemolytic anemia, pernicious anemia ofautoimmune atrophic gastritis, autoimmune encephalomyelitis, autoimmuneorchitis, Goodpasture's disease, autoimmune thrombocytopenia,sympathetic ophthalmia, myasthenia gravis, Graves' disease, primarybiliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis andmembranous glomerulopathy, those involving systemic autoimmune disorders(e.g. systemic lupus erythematosus, rheumatoid arthritis, Sjogren'ssyndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemicsclerosis, polyarteritis nodosa, multiple sclerosis and bullouspemphigoid) and other O-cell (humoral) or T-cell autoimmune diseases(including Kogan syndrome), ankylosing spondylitis, Wegener's Granuloma,autoimmune alopecia, type I diabetes or juvenile-onset diabetes orthyroiditis;Cancer or tumor, including digestive/gastrointestinal cancer, colorectalcancer, liver cancer, skin cancer (including mast cell tumor andsquamous cell carcinoma), breast cancer, ovarian cancer, prostatecancer, lymphoma, leukemia (including acute myeloid leukemia and chronicmyeloid leukemia), kidney cancer, lung cancer, muscle cancer, bonecancer, bladder cancer, brain cancer, melanoma (including oral andmetastatic melanoma), Kaposi's sarcoma, myeloma (including multiplemyeloma), myeloproliferative disorders, proliferative diabeticretinopathy or disorders related to angiogenesis (including solidtumors);Diabetes, including type I diabetes or diabetic complications;Eye diseases, disorders or conditions, including autoimmune diseases ofeyes, keratoconjunctivitis, vernal conjunctivitis, uveitis (includinguveitis and lens uveitis related to Behcet's disease), keratitis,herpetic keratitis, keratitis conus, corneal epithelial dystrophy,leukoplakia, ocular pemphigus, Moran ulcer, scleritis, Grave's eyedisease, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dryeye), blisters, iridocyclitis, sarcoidosis, endocrine ophthalmopathy,sympathetic ophthalmia, allergic conjunctivitis, or ocularneovascularization;Intestinal inflammation, allergies or conditions, including Crohn'sdisease and/or ulcerative colitis, inflammatory bowel disease, celiacdisease, proctitis, eosinophilic gastroenteritis or mastocytosis;Neurodegenerative diseases, including motor neuron disease, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, neurodegenerative disease caused by cerebralischemia or traumatic injury, stroke, glutamate neurotoxicity orhypoxia; stroke ischemia/reperfusion injury, myocardial ischemia, renalischemia, heart attack, cardiac hypertrophy, atherosclerosis andarteriosclerosis, organ hypoxia or platelet aggregation;Skin diseases, conditions or disorders, including atopic dermatitis,eczema, psoriasis, scleroderma, itching or other pruritic conditions,vitiligo, hair loss;Allergies, including mammalian allergic dermatitis (including equineallergic diseases, such as bite allergies), summer eczema, Culexmosquito itch syndrome (sweet itch), emphysema, inflammatory airwaydisease, recurrent airway obstruction, airway overreaction, or chronicobstructive pulmonary disease;Asthma and other obstructive airway diseases, including chronic orrefractory asthma, advanced asthma, bronchitis, bronchial asthma,allergic asthma, endogenous asthma, exogenous asthma or dusty asthma;andTransplant rejection, including islet transplant rejection, bone marrowtransplant rejection, graft versus host disease, organ and celltransplant rejection (for example bone marrow, cartilage, cornea, heart,intervertebral disc, pancreatic islets, kidney, limbs, liver, lung,muscle, myoblasts, nerve, pancreas, skin, small intestine or trachea) orxenotransplantation.

In a fourth aspect, the present disclosure provides a method fortreating JAK-related diseases or disorders, the method comprisingadministrating a therapeutically effective amount of the compound asdescribed above or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof, or thecomposition as described above to patients in need. Among them, thepatient is preferably a mammal, and more preferably a human patient. Theroute of administration can be oral, topical (including but not limitedto external application, spraying, and the like), parenteral (includingsubcutaneous, intramuscular, cortical, and intravenous) administration,bronchial administration, or nasal administration. Among them, it ispreferably administered orally or topically. It is more preferablyadministered orally.

Unexpectedly, the compound of the present disclosure demonstratedexcellent efficacy as a JAK kinase inhibitor in experiments that issuperior to existing JAK kinase inhibitors, such as Filgotinib, and hadgood safety potentially.

Preferably, the present disclosure provides the following embodiments:

1. A compound of Formula (G),

or an isotopically labeled compound thereof, or an optical isomerthereof, a geometric isomer thereof, a tautomer thereof or a mixture ofvarious isomers, or a pharmaceutically acceptable salt thereof, or aprodrug thereof, or a metabolite thereof,in whichL is C═O, O═S═O, CH₂ or a linkage; andX₁ is N or CR₁₄; andX₂ is N or CR₁₅; andX₃ is N or CR₁₆; andR₁₄, R₁₅, R₁₆ are each independently selected from H, —OH, —SH, —CN,halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl,C₅₋₇ aryl, 5-7 membered heteroaryl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂),—C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂,—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the—S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, and 3-7membered heterocycloalkyl are optionally substituted with 1, 2 or 3substitutes selected from halogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN,C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄ hydroxyalkyl, —S—C₁₋₄ alkyl, —C(═O)H,—C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄ alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄alkyl)₂, —N(C₁₋₄ alkyl)(C(═O) C₁₋₄ alkyl), C₁₋₄haloalkyl, C₁₋₄ alkoxyand C₁₋₄ haloalkoxy; andR₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —SR₁₂, —OR₁₂, —CN, halogen, —NO₂,—SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl or C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclyl,C₅₋₁₁bicycloalkyl, or 5-11 membered bicyclic heteroalkyl, and R₁₃ issubstituted with 0, 1, 2, 3 or 4 R₁(s), in which R₁₇, and R₁₈ are eachindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₅₋₇aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 memberedbicyclic heteroaryl, 11-15membered tricyclyl, C₅₋₁₁bicycloalkyl, and5-11 membered bicyclic heteroalkyl and are optionally substituted withone or more substitutes each independently selected from —OH, —CN, —SH,halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, 7-11 membered bicyclic heteroaryl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂),—C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂,—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, wherein the—S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, C₅₋₇aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 memberedbicyclic heteroaryl are optionally substituted with 1, 2 or 3substitutes each independently selected from halogen, —CN, —OH, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl,—N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂,—C(═O)—N(R₉)(R₁₀), —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and—OR₁₂; or R₁₇, R₁₈ and the N atom connected thereto together form a 3-14membered ring; and0, 1, 2, 3 or 4 R₂(s) are present in formula (G), and R₂ is selectedfrom H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄ alkyl, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl,—N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂,—C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂and —OR₁₂, in which the —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, and 7-11 membered bicyclic heteroaryl are each optionallysubstituted with 1, 2 or 3 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂; andR₁ is selected from H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄alkyl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₃₋₇cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl,11-15membered tricyclyl, C₅₋₁₁bicycloalkyl, 5-11 membered bicyclicheteroalkyl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀),—C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂),—S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the —S—C₁₋₄ alkyl, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, and C₁₋₈ alkoxy are optionallysubstituted with 1, 2, 3, or 4 R₃(s), and in which the C₃₋₇ cycloalkyl,3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl,C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclic heteroaryl areoptionally substituted with 1, 2, 3, or 4 R₄(s); andR₃ and R₄ are each independently selected from H, halogen, —OH, —NO₂,—CN, —SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclicheteroaryl, —N(R₅)(R₆), —N(R₁₁)(C(═O)R₁₂), —CON(R₇)(R₈), —C(═O)—R₁₂,—C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂and —OR₁₂, in which the C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-10 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, and 7-11 membered bicyclic heteroaryl are each optionallysubstituted with 1, 2, 3 or 4 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₆ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂; andR₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ are each independently H orselected from the group consisting of C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₃₋₇cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein the substituents included inthe above group are each optionally substituted with 1, 2, 3 or 4substituent(s) each independently selected from the group consisting ofhalogen, —CF₃, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, oxo, C₁₋₄ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₄ hydroxyalkyl, —S—C₁₋₄alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄ alkyl, —C(═O)—NH₂,—C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxy and C₁₋₄ haloalkoxy.

2. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 1, which is an isotopically labeled compound of the compoundof formula (G), wherein all Hs are each independently optionallysubstituted with D.

3. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 1, wherein X₁ is N.

4. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 1, wherein X₂ is N.

5. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 1, wherein X₃ is N.

6. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 1, wherein X₁ is CR₁₄, X₂ is N or CR₁₅, and X₃ is CR₁₆.

7. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 1, wherein X₁, X₂ and X₃ are the same.

8. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 2, wherein X₁, X₂ and X₃ are the same.

9. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 1, wherein X₁, X₂ and X₃ are CH.

10. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 8, wherein X₁, X₂ and X₃ are CH.

11. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein L is C═O, O═S═O or CH₂.

12. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein R₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy,—OH, —SH, —CN, halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, or C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl,11-15 membered tricyclyl, C₅₋₁₁bicycloalkyl, or 5-11 membered bicyclicheteroalkyl, and R₁₃ is substituted with 0, 1, 2, 3 or 4 R₁(s), in whichR₁₇ and R₁₈ are each independently selected from H, C₁₋₆ alkyl, C₁₋₆alkoxy, C₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, C₅₋₇ aryl, and 5-7membered heteroaryl, and are optionally substituted with one or more of—OH, —CN, —SH, halogen, —NO₂,— and SF₅.

13. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein R₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy,—OH, —SH, —CN, halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl, or11-15 membered tricyclyl, and R₁₃ is substituted with 0, 1, 2, 3 or 4R₁(s).

14. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein R₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy,C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl,or 5-7 membered heteroaryl, and R₁₃ is substituted with 0, 1, 2, 3, or 4R₁(s).

15. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein R₁₃ is —N(R₁₇)(R₁₈), C₁₋₆ alkoxy,C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or5-6 membered heteroaryl, and R₁₃ is substituted with 0, 1, 2, or 3R₁(s).

16. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein R₁₇ and R₁₈ are each independentlyselected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₃₋₇ heterocycloalkyl,and are optionally substituted with one or more of —OH, —CN, —SH,halogen, —NO₂,— and SF₅.

17. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein R₁₇, R₁₈ and the N atom connectedthereto together form a 4-10 membered ring.

18. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein L is C═O, and R₁₃ is —N(R₁₇)(R₁₈),CT 6 alkoxy, —OH, —SH, —CN, halogen, —NO₂, —SF₅, or —S—C₁₋₄ alkyl, andR₁₃ is substituted with 0, 1, 2, 3 or 4 R₁(s) in which R₁₇ and R₁₈ areeach independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇cycloalkyl, C₃₋₇ heterocycloalkyl, C₅₋₇ aryl, and 5-7 memberedheteroaryl, and are optionally substituted with one or more of —OH, —CN,—SH, halogen, —NO₂,— and SF₅, or R₁₇, R₁s and the N atom connectedthereto together form a 4-10 membered ring.

19. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein 1, 2 or 3 R₂(s) are present and R₂is selected from H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄ alkyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, and 4-10 membered heterocycloalkyl, in which the—S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2 or 3substituent(s) each independently selected from the group consisting ofhalogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.

20. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein 1, 2 or 3 R₂(s) are present, and R₂is selected from halogen, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl in which theC₁₋₆ alkyl and C₃₋₆ cycloalkyl are each optionally substituted with 1, 2or 3 substituent(s) each independently selected from the groupconsisting of halogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.

21. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 15, wherein 1 or 2 R₂(s) are present, and R₂ is selected fromhalogen, and C₁₋₆ alkyl.

22. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein R₁₃ is substituted with 0 or 1 R₁,and R₁ is selected from halogen, —OH, C₁₋₆ alkyl, 5-7 memberedheterocycloalkyl, and C₃₋₇ cycloalkyl, in which the C₁₋₆ alkyl isoptionally substituted with 1, 2, or 3 R₃(s) and in which the 5-7membered heterocycloalkyl, and C₃₋₇ cycloalkyl is optionally substitutedwith 1, 2, 3 or 4 C₁₋₃ alkyl.

23. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 10, wherein the compound is selected from agroup consisting of:

-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinylpyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,    4H,6H)-yl)(1-methylpiperidin-4-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,    4H,6H)-yl)(5-(4-methylpiperzin-1-yl)pyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperzin-1-yl)pyrazin-2-yl)ketone;-   5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5    (1H,4H,6H)-yl)ketone;-   4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5    (1H,4H,6H)-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxylcyclobutyl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone;-   (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;-   5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;-   5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one;-   2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)ketone;-   Azetidin-1-yl((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperzin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperzin-1-yl)ketone;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;-   (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl) (3-hydroxylpyrrolidin-1-yl)ketone;-   Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;-   (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl) (3-hydroxylpyrrolidin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylAzetidin-1-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl)(4-hydroxylpiperidin-1-yl)ketone;-   2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide;-   2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide;-   2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)azetidine-3-nitrile;-   1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidin-3-nitrile;-   2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   Methyl    2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate;-   Ethyl    2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-carboxylate;-   (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;-   3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile;-   2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl)(2,6-diazaspiro[3.3]heptan-2-yl)ketone;-   (S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol;    and-   (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol.

24. A pharmaceutical composition, comprising the compound, or anisotopically labeled compound thereof, or an optical isomer thereof, ageometric isomer thereof, a tautomer thereof or a mixture of variousisomers, or a pharmaceutically acceptable salt thereof, or a prodrugthereof, or a metabolite thereof according to any one of embodiments 1to 23, and one or more pharmaceutically acceptable carriers, adjuvantsor excipients.

25. Use of the compound, or isotopically labeled compound thereof, oroptical isomer thereof, geometric isomer thereof, a tautomer thereof ora mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 1 to 23 or the pharmaceutical composition ofembodiment 24 in the manufacture of a medicament for the treatmentand/or prevention of a JAK-related disease or disorder.

26. The use according to embodiment 25, wherein the JAK-related diseaseor disorder is selected from the group consisting of arthritis,autoimmune diseases or disorders, cancer or tumor, diabetes, eyediseases, disorders or conditions, intestinal inflammation, allergies orconditions, neurodegenerative diseases, skin diseases, conditions ordisorders, allergies, asthma and other obstructive airway diseases, andtransplant rejection.

27. A compound of Formula (I),

or an isotopically labeled compound thereof, or an optical isomerthereof, a geometric isomer thereof, a tautomer thereof or a mixture ofvarious isomers, or a pharmaceutically acceptable salt thereof, or aprodrug thereof, or a metabolite thereof,in whichL is C═O, O═S═O, CH₂ or a linkage; and

X is CH or N;

The ring A is C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl,5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclicheteroaryl, or 11-15 membered tricyclyl;0, 1, 2, 3 or 4 R₁(s) are present in formula (I), and R₁ is selectedfrom H, halogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy,C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclic heteroaryl,in which the C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, and C₁₋₈ alkoxy areoptionally substituted with 1, 2, 3 or 4 R₃(s), and in which the C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl areoptionally substituted with 1, 2, 3 or 4 R₄(s),0, 1, 2, 3 or 4 R₂(s) are present in formula (I), and R₂ is selectedfrom H, halogen, —OH, —NO₂, —CN, —SF₅, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀),—C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂),—S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the C₁₋₆ alkyl, C₃₋₇cycloalkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2 or 3 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂;R₃ is selected from halogen, cyano, C₁₋₃ alkyl, hydroxy, C₁₋₆ alkoxy,—N(R₅)(R₆), —CON(R₇)(R₈) or 3-7 membered heterocycloalkyl, in which the3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or4 R₄(s);R₄ is selected from halogen, C₁₋₃ alkyl, hydroxyl, C₁₋₆ alkoxy, —NH₂,—NHCH₃ or —N(CH₃)₂;R₅, R₆, R₇, RX are each independently hydrogen or C₁₋₄ alkyl;R₉ is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₃₋₇ cycloalkyl;R₁₀ is H or selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein each substituent included inthe above group is optionally substituted with 1, 2, 3 or 4substituent(s) each independently selected from the group consisting of—OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄hydroxyalkyl, —S—C₁₋₄ alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxyand C₁₋₄ haloalkoxy;R₁₁ is selected from H, C₁₋₄ alkyl and C₃₋₇ cycloalkyl; andR₁₂ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₇cycloalkyl, 4- to 14-membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein each substituent included inthe above group is optionally substituted with 1, 2 or 3 substituent(s)each independently selected from the group consisting of halogen, —CF₃,—CN, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, oxo, —S—C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy andC₁₋₄ haloalkoxy.

28. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 27, wherein L is C═O, O═S═O or CH₂.

29. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 27, wherein X is CH.

30. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 27 to 29, wherein the ring A is C₃₋₇ cycloalkyl, 3-7membered heterocycloalkyl, C₅₋₇ aryl, or 5-7 membered heteroaryl.

31. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 27 to 29, wherein the ring A is 5-6 memberedheteroaryl, or phenyl.

32. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 27 to 29, wherein 0, or 1 R₁ is present, and R₁ isselected from C₁₋₆ alkyl, and 5-7 membered heterocycloalkyl in which theC₁₋₆ alkyl is optionally substituted with 1 or 2 R₃, and in which the5-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or4 C₁₋₃ alkyl.

33. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 27 to 29, wherein 1 or 2 R₂(s) are present, and R₂ isselected from halogen, C₁₋₆ alkyl and C₃₋₆ cycloalkyl, in which the C₁₋₆alkyl and C₃₋₆ cycloalkyl are each optionally substituted with 1, 2 or 3substituent(s) each independently selected from the group consisting ofhalogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.

34. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 27 to 29, wherein

L is C═O, and O═S═O; X is CH;

The ring A is 5-7 membered heteroaryl or C₅₋₇ aryl;0, 1, 2, 3 or 4 R₁(s) are present in formula (I), and R₁ is selectedfrom C₁₋₈ alkyl, and 3-7 membered heterocycloalkyl, in which the C₁₋₈alkyl is optionally substituted with 1, 2, 3 or 4 R₃(s), and in whichthe 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3or 4 R₄(s),1, 2, or 3 R₂(s) are present in formula (I), and R₂ is selected from H,halogen, —OH, —NO₂, —CN, —SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀),—C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂),—S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the C₁₋₆ alkyl, C₃₋₇cycloalkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2 or 3 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂;R₃ is selected from halogen, cyano, C₁₋₃ alkyl, hydroxy, C₁₋₆ alkoxy,—N(R₅)(R₆), —CON(R₇)(R₈) or 3-7 membered heterocycloalkyl, in which the3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or4 R₄(s);R₄ is selected from halogen, C₁₋₃ alkyl, hydroxyl, C₁₋₆ alkoxy, —NH₂,—NHCH₃ or —N(CH₃)₂;R₅, R₆, R₇, R₈ are each independently hydrogen or C₁₋₄ alkyl;R₉ is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₃₋₇ cycloalkyl;R₁₀ is H or selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein each substituent included inthe above group is optionally substituted with 1, 2, 3 or 4substituent(s) each independently selected from the group consisting of—OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄hydroxyalkyl, —S—C₁₋₄ alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxyand C₁₋₄ haloalkoxy;R₁₁ is selected from H, C₁₋₄ alkyl and C₃₋₇ cycloalkyl; andR₁₂ is selected from the group consisting of C₁₋₆ alkyl, C₃₋₇cycloalkyl, 4- to 14-membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein each substituent included inthe above group is optionally substituted with 1, 2 or 3 substituent(s)each independently selected from the group consisting of halogen, —CF₃,—CN, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, oxo, —S—C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy andC₁₋₄ haloalkoxy.

35. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 34, wherein the ring A is 5-6 membered heteroaryl, or phenyl.

36. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 34, wherein 0 or 1 R₁ is present, and R₁ is selected fromC₁₋₆ alkyl, and 5-7 membered heterocycloalkyl, wherein the C₁₋₆ alkyl isoptionally substituted by 1 or 2 R₃, and wherein the 5-7 memberedheterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 C₁₋₃alkyl.

37. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toembodiment 34, wherein 1 or 2 R₂(s) are present, and R₂ is selected fromhalogen, C₁₋₆ alkyl and C₃₋₆ cycloalkyl, wherein the C₁₋₆ alkyl and C₃₋₆cycloalkyl are each optionally substituted with 1, 2 or 3 substituent(s)each independently selected from the group consisting of halogen, —OH,—NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyand C₁₋₄ haloalkoxy.

38. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 27 to 29, wherein the compound is selected from agroup consisting of:

-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinpyrazin-2-yl)ketone;-   (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5    (1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone;-   5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidin-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol;-   5-ethyl-2-fluoro-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol;-   3-ethyl-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol;-   5-ethyl-2-fluoro-4-(3-(5-(bemzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;    and-   5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2-methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol.

39. A pharmaceutical composition, comprising the compound, or anisotopically labeled compound thereof, or an optical isomer thereof, ageometric isomer thereof, a tautomer thereof or a mixture of variousisomers, or a pharmaceutically acceptable salt thereof, or a prodrugthereof, or a metabolite thereof according to any one of embodiments27-38, and one or more pharmaceutically acceptable carriers, adjuvantsor excipients.

40. Use of the compound, or isotopically labeled compound thereof, oroptical isomer thereof, geometric isomer thereof, a tautomer thereof ora mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according to anyone of embodiments 27-38 or the pharmaceutical composition of embodiment39 in the manufacture of a medicament for the treatment and/orprevention of a JAK-related disease or disorder.

41. The use according to embodiment 40, wherein the JAK-related diseaseor disorder is selected from the group consisting of arthritis,autoimmune diseases or disorders, cancer or tumor, diabetes, eyediseases, disorders or conditions, intestinal inflammation, allergies orconditions, neurodegenerative diseases, skin diseases, conditions ordisorders, allergies, asthma and other obstructive airway diseases, andtransplant rejection.

The present invention will be further illustrated and described below inconjunction with the drawings and specific examples.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the NMR spectrum of compound MDI-2.

FIG. 2 shows the NMR spectrum of compound MDI-201.

FIG. 3 shows the NMR spectrum of compound MDI-202.

FIG. 4 shows the NMR spectrum of compound MDI-206.

FIGS. 5A to 5D show IC50 curve of JAK1 experiments for MDI-201, MDI-202,and MDI-206, in which Filgotinib was used as a positive control.

FIGS. 6A to 6D show IC50 curve of JAK2 experiments for MDI-201, MDI-202,and MDI-206, in which Filgotinib was used as a positive control.

FIGS. 7A to 7D show IC50 curve of JAK3 experiments for MDI-201, MDI-202,and MDI-206, in which Filgotinib was used as a positive control.

FIGS. 8A to 8D show IC50 curve of TYK2 experiments for MDI-201, MDI-202,and MDI-206, in which Filgotinib was used as a positive control.

EXAMPLES

The compounds of formula (G), the compounds of formula (G′) or thecompounds of formula (I) of the present disclosure can be synthesized byvarious methods familiar to those skilled in the art of organicsynthesis. The following specific examples give some exemplary synthesismethods of the compounds of formula (G), the compounds of formula (G′)or the compounds of formula (I), and these methods are well-known in thefield of synthetic chemistry. Obviously, referring to the exemplaryembodiments of the present application, those skilled in the art canappropriately adjust reactants, reaction conditions, and protectivegroups to easily design other synthetic routes for compounds of formula(G), formula (G′) or formula (I).

The following further describes the present disclosure in conjunctionwith examples. Nevertheless, these examples do not limit the scope ofthe present disclosure.

Example1:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone(MDI-2)

Synthetic Route of Target Compound 8 (i.e. MDI-2):

Synthetic Route of Intermediate 10

Synthetic Route of Intermediate 16

Synthetic Route of Intermediate 20

Synthesis Method: Synthesis of Intermediate1:6-Bromo-1H-Indazole-3-Formaldehyde

Sodium nitrite (14.00 g, 200 mmol) was dissolved in 75 ml DMF and 100 mlwater, and then cooled to 0° C. Under nitrogen protection, 3N HCl (23ml, 68.9 mmol) was slowly added dropwise and after addition, thereaction was carried out for 10 minutes. At 0° C., to the reactionsolution, 6-bromoindole (5.00 g, 25.5 mmol) in DMF (35 ml) was slowlyadded dropwise. After the dropwise addition was complete, the reactionwas continued at room temperature overnight. The resulting mixture wasextracted with ethyl acetate 3 times, and then the organic phases werecombined, washed 3 times with water, washed with saturated brine, driedover anhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford the intermediate 1, with a yield of 83.6%.

¹H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.80(d, J=4.0 Hz, 1H), 7.52 (dd, J=8.0 Hz, J=4.0 Hz, 1H).

Synthesis of Intermediate 2: 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-formaldehyde

Intermediate 1 (1.56 g, 6.93 mmol) was dissolved in dry tetrahydrofuran,and then cooled to 0° C. Sodium hydride (0.33 g, 8.32 mmol) was addedslowly, the reaction was carried out at room temperature for 1 hour, andthen cooled to 0° C. After that, 2-(trimethylsilyl)ethoxymethyl chloride(1.73 g, 10.40 mmol) was added drop wise and the reaction was carriedout at room temperature overnight. The reaction was quenched by addingwater. The resulting mixture was extracted twice with ethyl acetate, andthe organic phases were combined and washed with water and saturatedbrine, dried over anhydrous sodium sulfate, concentrated, and purifiedby silica gel column to afford Intermediate 2, with a yield of 49.2%.

¹H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 8.22 (dd, J=8.0 Hz, J=4.0 Hz1H), 7.88 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 7.52 (dd, J=4.0 Hz, J=4.0 Hz,1H), 5.81 (s, 2H), 3.63-3.58 (m, 2H), 0.97-0.93 (m, 2H), 0.04 (s, 9H).

Synthesis of Intermediate 16: Tert-butyl3,4-diaminopyrrolidinyl-1-carboxylate 1. Synthesis of Intermediate 11:Tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate

3-pyrroline (10.0 g, 0.15 mol) was dissolved in 400 ml dichloromethaneand triethylamine (40.6 ml, 0.29 mol), and then cooled to 0° C. (Boc)₂O(37.9 g, 0.17 mol) was slowly added. The reaction was carried out atroom temperature overnight. Water was added and the mixture wasextracted twice with dichloromethane. The organic phases was combined,washed with water three times, washed with saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford Intermediate 11 with a yield of 91.0%.

2. Synthesis of Intermediate 12: Tert-butyl6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

Intermediate 11 (24.5 g, 0.15 mol) was dissolved in 450 ml ofdichloromethane, and then cooled to 0° C. M-chloroperoxybenzoic acid(37.5 g, 0.22 mol) was slowly added in batches. The reaction was carriedout at room temperature overnight. After that, saturated sodiumthiosulfate (40 ml) was added, and then stirred for 30 minutes. Theaqueous phase was extracted twice with dichloromethane, washed withsaturated potassium carbonate solution, water and saturated brine, driedover anhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford Intermediate 12 with a yield of 84.9%.

¹H NMR (400 MHz, CDCl3) δ 3.85 (d, J=12.0 Hz, 1H), 3.77 (d, J=12.0 Hz,1H), 3.69-3.67 (m, 2H), 3.36-3.30 (m, 2H), 1.45 (s, 9H).

3. Synthesis of Intermediate 13: Tert-butyl 3-azido-4-hydroxylpyrrolidinyl-1-carboxylate

Intermediate 12 (20.8 g, 0.12 mol) was dissolved in 150 ml 1,4-dioxaneand 50 ml water, and then sodium azide (24.0 g, 0.37 mol) was added. Themixture was heated to 106° C. and reacted for 18 hours, then cooled toroom temperature, followed by adding 100 ml of saturated brine. Theresulting mixture was extracted with dichloromethane (250 ml*4), and theorganic phases were combined, washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated to afford Intermediate 13,with a yield of 100%.

¹H NMR (400 MHz, CDCl3) δ 4.27-4.24 (m, 1H), 3.94 (s, 1H), 3.73-3.59 (m,2H), 3.41-3.36 (m, 2H), 1.47 (s, 9H).

4. Synthesis of Intermediate 14: Tert-butyl 3-azido-4-((methanesulfonyl)oxy)pyrrolidinyl-1-carboxylate

Intermediate 13 (28.0 g, 0.12 mol) was dissolved in 350 ml ofdichloromethane and triethylamine (37.3 g, 0.37 mol), and cooled to 0°C., followed by slowly adding methanesulfonyl chloride (16.9 g, 0.15mol) dropwise. After the addition, the reaction was carried out at roomtemperature for 2 hours, the reaction was quenched with water, and theresulting mixture was extracted twice with dichloromethane. The organicphases was combined, washed with saturated sodium bicarbonate solution,water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated to afford Intermediate 14, with a yield of 98.0%.

5. Synthesis of Intermediate 15: Tert-butyl3,4-diazidopyrrolidinyl-1-carboxylate

Intermediate 14 (36.9 g, 0.12 mol) was dissolved in 250 ml DMF, to whichsodium azide (23.5 g, 0.36 mol) was added. The mixture was heated to 90°C., reacted for 2 days, and cooled to room temperature, following byadding 750 ml of water. The resulting mixture was extracted with butyltert-butyl ether (400 ml*4), and the organic phases were combined,washed with saturated brine, dried with anhydrous sodium sulfate, andpurified by silica gel column to afford Intermediate 15 with a yield of62.2%.

6. Synthesis of Intermediate 16: Tert-butyl3,4-diaminopyrrolidinyl-1-carboxylate

Intermediate 15 (18.9 g, 0.08 mol) was dissolved in 200 ml methanol, and10% Pd/C was added where it was replaced with hydrogen 3 times. Themixture was heated to 40° C., and reacted for 2 days. The resultingmixture was filtered and concentrated to afford Intermediate 16, with ayield of 78%.

¹H NMR (400 MHz, CDCl3) δ 3.51-3.49 (m, 2H), 3.40-3.36 (m, 2H),3.21-3.11 (m, 2H), 1.47 (s, 9H).

Synthesis of Intermediate 3: Tert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)3,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 2 (1.56 g, 6.93 mmol) and tert-butyl3,4-diaminopyrroline-1-carboxylate (1.56 g, 6.93 mmol) were dissolved in5 ml of hexafluoroisopropanol and heated to 40° C. for 2 days. Theresulting mixture was concentrated and purified by a silica gel columnto afford Intermediate 3 with a yield of 54.7%.

Synthesis of Intermediate 4: Tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Oxalyl chloride (0.53 g, 4.20 mmol) was dissolved in dry 15 mldichloromethane, and cooled to −78° C. under the protection of nitrogen.DMSO (0.61 g, 7.84 mmol) was slowly added dropwise. After the additionwas complete, it was allowed to react for 30 minutes. Intermediate 3(1.00 g, 1.87 mmol) in dichloromethane was slowly added dropwise. Afterthe dropwise addition, it was allowed to react for 30 minutes. Drytriethylamine (1.89 g, 18.66 mmol) was added slowly dropwise, and it wasallowed to react for 10 minutes. The temperature was increased slowlyand the reaction was carried out at room temperature for 2 hours. Thereaction was quenched with saturated ammonium chloride solution and theresulting mixture was extracted twice with dichloromethane, and theorganic layers were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford Intermediate 4 with a yield of 36.3%.

¹H NMR (400 MHz, CDCl3) δ 8.36 (d, J=4.0 Hz, 1H), 7.78 (d, J=4.0 Hz,1H), 7.44 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 5.69 (s, 2H), 4.64-4.52 (m, 4H),3.67-3.56 (m, 2H), 1.56 (s, 9H), 0.95-0.89 (m, 2H), 0.03 (s, 9H).

Synthesis of Intermediate 5: Tert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Intermediate 4 (110 mg, 0.21 mmol) was dissolved in dry tetrahydrofuran,and cooled to 0° C. Sodium hydride (12.3 mg, 0.31 mmol) was added and itallowed to react at room temperature for 30 minutes. The mixture wascooled to 0° C. 2-(tri methylsilyl)ethoxymethyl chloride (41.2 mg, 0.25mmol) was added slowly dropwise, and it allowed to react at roomtemperature for 4 hours. The reaction was quenched with water and theresulting mixture was extracted twice with ethyl acetate. The organicphases were combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to intermediate 5 with a yield of 73.1%.

¹H NMR (400 MHz, CDCl3) δ 8.41-8.36 (m, 1H), 7.79 (s, 1H), 7.44 (dd,J=8.0 Hz, J=4.0 Hz, 1H), 5.94 (d, J=12.0 Hz, 2H), 5.73 (s, 2H),4.65-4.52 (m, 4H), 3.63-3.57 (m, 4H), 1.56 (s, 9H), 0.96-0.91 (m, 4H),0.03 (s, 18H)).

Synthesis of Intermediate 10: 5-(piperidin-1-yl)pyrazine-2 carboxylicacid 1. Synthesis of Intermediate 9: Methyl5-(piperidin-1-yl)pyrazine-2-carboxylate

Methyl 5-chloro-pyrazine-2-carboxylate (1.72 g, 10 mmol) was dissolvedin 10 ml DMF, and N,N-diisopropylethylamine (4.3 ml, 25.0 mmol) andpiperidine hydrochloride (1.45 g, 12.0 mmol) were added. The mixture wasstirred overnight at room temperature. Under vigorous stirring, waterwas added. A solid was precipitated, filtered, and the filter cake waswashed with water, and dried to afford Intermediate 9 with a yield of80.0%.

2. Synthesis of Intermediate 10: 5-(piperidin-1-yl)pyrazin-2-carboxylicacid

Intermediate 9 (430 mg, 1.95 mmol) was dissolved in 20 ml oftetrahydrofuran and 20 ml of water, to which lithium hydroxide (163 mg,3.88 mmol) was added. The reaction was carried out at room temperaturefor 4 hours. The mixture was concentrated by distilling offtetrahydrofuran under reduced pressure, and the pH was adjusted to 4with 1N HCl. A solid precipitated, filtered, and the filter cake waswashed with water, and dried to afford Intermediate 10 with a yield of91.5%.

¹H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.02 (s, 1H), 3.76-3.73 (m, 4H),1.78-1.65 (m, 6H).

Synthesis of Intermediate 6:(2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone

Intermediate 10 (34.3 mg, 0.17 mmol) and N,N-diisopropylethylamine (58.2mg, 0.45 mmol) were dissolved in DMF, HATU (85.7 mg, 0.22 mmol) wasadded, and the reaction was carried out at room temperature for 10minutes. Intermediate 5 (100 mg, 0.15 mmol) was dissolved in 5 ml ofdichloromethane, to which 1 ml of trifluoroacetic acid was added. Themixture was stirred at room temperature for 30 minutes, and concentratedto give a residue. The residue was dissolved in dichloromethane and wasconcentrated to dryness, which was repeated 3 times. The resultingresidue was dissolved in DMF and was then slowly added to the previousreaction solution. It was allowed to react overnight at roomtemperature. The reaction was quenched with water, and the resultingmixture was extracted twice with ethyl acetate. The organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate 6 with a yield of 57.3%.

¹H NMR (400 MHz, CDCl₃) δ 8.87 (d, J=8.0 Hz, 1H), 8.41-8.37 (m, 1H),8.09-8.04 (m, 1H), 7.80 (s, 1H), 7.44-7.41 (m, 1H), 5.96 (s, 2H), 5.75(d, J=8.0 Hz, 2H), 5.28 (s, 1H), 5.19 (s, 1H), 4.99 (s, 1H), 4.91 (s,1H), 3.74-3.68 (m, 4H), 3.67-3.64 (m, 2H), 3.63-3.59 (m, 2H), 1.71-1.68(m, 6H), 0.95-0.91 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

Synthesis of Intermediate 20:(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane 1.Synthesis of Intermediate 17: 5-ethyl-2-fluorophenol

5-bromo-2-fluorophenol (200.0 mg, 1.05 mmol) andbis(tri-tert-butylphosphorus) palladium (10.7 mg, 0.02 mmol) wasdissolved in 10 ml THF. The atmosphere was replaced with nitrogen, whichwas repeated 3 times. The temperature was lowered to 10-20° C. 1 mol/Ldiethyl zinc solution (2.3 ml, 2.30 mmol) was added dropwise. After theaddition was completed, the temperature was heated up to 50° C. It wasallowed to react overnight, and the temperature was cooled to 0° C. Thereaction was quenched with water, and filtered with celite. The celitepad was washed with ethyl acetate. The resulting filtrate was extractedwith ethyl acetate, and the organic phases were combined, washed withsaturated sodium chloride solution, and dried over anhydrous sodiumsulfate. After drying, it was concentrated and separated by columnchromatography to afford an oily liquid with a yield of 65.1%.

¹H NMR (400 MHz, CDCl₃) δ6.97 (d, J=8.0 Hz, 1H), 6.85 (d, J=12.0 Hz,1H), 6.69-6.65 (m, 1H), 2.61-2.55 (m, 2H), 1.21 (t, J=8.0 Hz, 3H).

2. Synthesis of Intermediate 18: 4-bromo-5-ethyl-2-fluorophenol

Intermediate 17 (200.1 mg, 1.43 mmol) was dissolved in 6 ml ofacetonitrile, to which CuBr₂ (957.5 mg, 4.29 mmol) was added. Themixture was stirred at room temperature for 3 hours. The reaction wasquenched with water, extracted with ethyl acetate, and the organic phasewas washed with saturated sodium chloride solution and dried overanhydrous sodium sulfate. It was concentrated and separated by columnchromatography to afford a colorless oil, yield: 78.1%.

¹H NMR (400 MHz, CDCl3) δ7.25 (d, J=12.0 Hz, 1H), 6.89 (d, J=12.0 Hz,1H), 2.69-2.63 (m, 2H), 1.19 (t, J=12.0 Hz, 3H).

3. Synthesis of Intermediate 19:(2-((4-bromo-5-ethyl-2-fluorophenoxy)methoxy)ethyl)trimethylsilane

Intermediate 18 (220.0 mg, 1.00 mmol) was dissolved in 6 ml DCM, DIPEA(130.5 mg, 1.10 mmol) was added, and the temperature was reduced to 0°C. SEMC1 (168.2 mg, 1.10 mmol) was added dropwise at 0° C. After theaddition, the temperature was raised to room temperature, and it wasallowed to react for 8 hours. The reaction was quenched with water, andextracted with DCM. The organic phase was washed with saturated sodiumchloride solution, and dried over anhydrous sodium sulfate. It wasconcentrated to afford a colorless oil, the crude yield: 99.1%.

¹H NMR (400 MHz, CDCl3) δ7.26 (d, J=12.0 Hz, 1H), 6.89 (d, J=12.0 Hz,1H), 5.24 (s, 2H) 3.82-3.78 (m, 2H) 2.67-2.62 (m, 2H), 1.19 (t, J=12.0Hz, 3H), 0.98-0.94 (m, 2H), 0.01 (s, 9H).

4. Synthesis of Intermediate 20:(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane

Compound 19 (280.0 mg, 0.80 mmol), pinacol borate (206.1 mg, 0.80 mmol),Pd(dppf)Cl₂ (59.2 mg, 0.08 mmol) and KOAc (237.5 mg, 2.40 mmol) weredissolved in 1, 4-dioxane (6 ml). The atmosphere was replaced withnitrogen, which was repeated 3 times. The mixture was heated to 100° C.and it was allowed to react overnight. After the reaction was completed,it was quenched with water, extracted with ethyl acetate, and theorganic phase was washed with saturated sodium chloride solution, anddried over anhydrous sodium sulfate. It was concentrated and separatedby column chromatography to afford a colorless oil, yield: 56.2%.

¹H NMR (400 MHz, CDCl3) δ7.48 (d, J=12.0 Hz, 1H), 7.02 (d, J=8.0 Hz,1H), 5.28 (s, 2H), 3.82-3.78 (m, 2H) 2.89-2.83 (m, 2H), 1.35 (s, 12H),1.17 (t, J=8.0 Hz, 3H), 0.98-0.94 (m, 2H), 0.01 (s, 9H).

Synthesis of Intermediate 7:(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone

Intermediate 6 (65.0 mg, 0.09 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(40.9 mg, 0.10 mmol), Pd(dppf)Cl₂ (6.3 mg, 0.01 mmol) and potassiumphosphate (25.3 mg, 0.26 mmol) were dissolved in 1,4-dioxane (10 ml) andwater (2 ml). The atmosphere was replaced with nitrogen 3 times. Themixture was heated to 100° C., reacted overnight, and cooled to roomtemperature. Water was added and the mixture was extracted 2 times withethyl acetate. The organic phases were combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column to afford Intermediate 7 with a yield of52.8%.

¹H NMR (400 MHz, CDCl3) δ 8.87 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 8.54 (dd,J=8.0 Hz, J=20.0 Hz, 1H), 8.10 (dd, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.27(s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.00 (s, 2H),5.79 (d, J=4.0 Hz, 2H), 5.35 (s, 2H), 5.33 (s, 1H), 5.29 (s, 1H), 5.20(s, 1H), 5.01 (s, 1H), 3.91 (t, J=8.0 Hz, J=20.0 Hz, 2H), 3.76-3.74 (m,4H), 3.64-3.62 (m, 4H), 2.58 (t, J=8.0 Hz, J=16.0 Hz, 2H), 1.74-1.72 (m,6H), 1.10-1.06 (m, 3H), 0.95-0.91 (m, 6H), 0.06 (s, 9H), 0.04 (s, 9H),0.03 (s, 9H).

Synthesis of Compound 8 (i.e. MDI-2):(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone

Intermediate 7 (43.0 mg, 0.05 mmol) was dissolved in methanol (4 ml), towhich concentrated hydrochloric acid (2 ml) was added. The mixture washeated to 50° C., reacted for 6 hours, and concentrated. The resultingsolid was dissolved in 1 ml methanol, pH was adjusted to 8-9 with sodiumbicarbonate solution, and then the resulting mixture was extracted 4times with dichloromethane. The organic phases were combined, dried overanhydrous sodium sulfate, and purified by a preparation plate to afford4.5 mg of the final product with a yield of 18.0%.

¹H NMR (400 MHz, MeOD-d4) δ 8.67 (s, 1H), 8.28 (dd, J=8.0 Hz, J=4.0 Hz,1H), 8.21 (s, 1H), 7.40 (s, 1H), 7.18 (dd, J=8.0 Hz, J=4.0 Hz, 1H),6.96-6.89 (m, 2H), 5.14 (s, 2H), 4.82 (s, 2H), 3.76-3.73 (m, 4H), 2.58(dd, J=12.0 Hz, J=8.0 Hz, 2H), 1.76-1.66 (m, 6H), 1.10 (t, J=8.0 Hz,3H).

Example 2:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone(MDI-201)

Synthetic Route of MDI-201:

Synthesis Method:

Synthesis of Intermediate MDI-201-1: Methyl 5-morpholinepyrazin-2-carboxylate

Methyl 5-chloro-pyrazine-2-carboxylate (1.5 g, 8.7 mmol) was dissolvedin 10 ml DMF, and N,N-diisopropylethylamine (3.0 ml, 17.4 mmol) andmorpholine (0.91 g, 10.4 mmol) were added. The mixture was stirredovernight at room temperature. Under vigorous stirring, water was addedand a solid precipitated out, and filtered. The resulting filter cakewas washed with water, and dried to afford the intermediate MDI-201-1with a yield of 72.2%.

Synthesis of Intermediate MDI-201-2: 5-morpholinepyrazin-2-carboxylicacid

The intermediate MDI-201-1 (1.4 g, 6.27 mmol) was dissolved in 20 ml oftetrahydrofuran and 20 ml of water, lithium hydroxide (0.32 g, 7.53mmol) was added, and the reaction was carried out at room temperaturefor 4 hours. The reaction mixture was concentrated by distilling offtetrahydrofuran under reduced pressure and adjusted with 1N HCl to pH=4.A solid precipitated out, and filtered. The resulting filter cake waswashed with water, and dried to afford the intermediate MDI-201-2 with ayield of 99.1%.

¹H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.04 (s, 1H), 3.88-3.86 (m, 4H),3.80-3.77 (m, 4H).

Synthesis of Intermediate MDI-201-3:(2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone

The intermediate MDI-201-2 (27.4 mg, 0.13 mmol) andN,N-diisopropylethylamine (46.0 mg, 0.36 mmol) was dissolved in DMF, towhich HATU (67.8 mg, 0.18 mmol) was added. It was allowed to react atroom temperature for 10 minutes. Intermediate tert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (80mg, 0.12 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml oftrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and concentrated to dryness,which was repeated 3 times. The resulting residue was dissolved in DMF,and then slowly added to the previous reaction solution. It was allowedto react at room temperature overnight, and water was added to quenchthe reaction. The mixture was extracted twice with ethyl acetate and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified on asilica gel column to afford intermediate MDI-201-3 with a yield of47.8%.

¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J=8.0 Hz, 1H), 8.44-8.36 (m, 1H),8.10 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.46-7.41 (m, 1H), 5.96 (s, 2H),5.74 (d, J=4.0 Hz, 2H), 5.27 (s, 1H), 5.19 (s, 1H), 5.00 (s, 1H), 4.92(s, 1H), 3.90-3.88 (m, 4H), 3.75-3.72 (m, 4H), 3.64-3.58 (m, 4H),0.96-0.89 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

Synthesis of Intermediate MDI-201-4:(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone

The intermediate MDI-201-3 (43.0 mg, 0.06 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.1 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol)and potassium phosphate (36.2 mg, 0.17 mmol) were dissolved in1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced withnitrogen, which was repeated 3 times. The mixture was heated to 100° C.,reacted overnight, cooled to room temperature. Water was added and theresulting mixture was extracted with ethyl acetate twice. The organicphases were combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford intermediate MDI-201-4 with a yield of 40.9%.

¹H NMR (400 MHz, CDCl3) δ 8.91 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 8.52 (dd,J=8.0 Hz, J=16.0 Hz, 1H), 8.10 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.49 (s,1H), 7.27 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.00(s, 2H), 5.79 (d, J=4.0 Hz, 2H), 5.35 (s, 2H), 5.29 (s, 1H), 5.20 (s,1H), 5.02 (s, 1H), 4.94 (s, 1H)), 3.91-3.86 (m, 6H), 3.76-3.72 (m, 4H),3.65-3.61 (m, 4H), 2.58 (t, J=8.0 Hz, 2H), 1.10-1.03 (m, 3H), 0.95-0.91(m, 6H), 0.06 (s, 9H), 0.04 (s, 9H), 0.03 (s, 9H).

Synthesis ofMDI-201:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone

The intermediate MDI-201-4 (22.0 mg, 0.02 mmol) was dissolved inmethanol (4 ml), to which concentrated hydrochloric acid (2 ml) wasadded. The mixture was heated to 50° C., reacted for 6 hours, andconcentrated. The resulting solid was dissolved with 1 ml methanol, towhich 2 ml concentrated aqueous ammonia was added. The resulting mixturewas concentrated to a residue. The residue was dissolved in methanol andconcentrated to dryness, which was repeated 3 times. The resultingresidue was and purified by a preparation plate to afford 8 mg of thefinal product, with a yield of 61.9%.

¹H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 9.89 (s, 1H), 8.66 (d, J=4.0Hz, 1H), 8.38-8.33 (m, 2H), 7.42 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.06(d, J=12.0 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 5.05 (s, 2H), 4.72 (s, 2H),3.76-3.74 (m, 4H), 3.71-3.68 (m, 4H), 2.52 (dd, J=12.0 Hz, J=4.0 Hz,2H), 1.05 (t, J=8.0 Hz, 3H).

Example 3:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone(MDI-202)

Synthetic Route of MDI-202:

Synthesis Method:

Synthesis of Intermediate MDI-202-1:(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone

The intermediate 1-methyl-1H-pyrazole-4-carboxylic acid (16.5 mg, 0.13mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) were dissolvedin DMF, to which HATU (67.8 mg, 0.18 mmol) was added. It was allowed toreact at room temperature for 10 minutes. Intermediate tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(80 mg, 0.12 mmol) was dissolved in 5 ml dichloromethane, to which 1 mlof trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and was concentrated todryness, which was repeated 3 times. The resulting residue was dissolvedin DMF and then slowly added to the previous reaction solution. It wasallowed to react at room temperature overnight, and water was added toquench the reaction. The resulting mixture was extracted twice withethyl acetate, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, concentrated,and purified by silica gel column to afford intermediate MDI-202-1 witha yield of 41.3%.

¹H NMR (400 MHz, CDCl3) δ 8.43 (dd, J=8.0 Hz, J=20.0 Hz, 1H), 7.98 (d,J=4.0 Hz, 2H), 7.81 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 5.96 (s, 2H), 5.75(s, 2H), 5.02-4.85 (m, 4H), 4.01 (s, 3H), 3.64-3.59 (m, 4H), 0.97-0.91(m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

Synthesis of intermediate MDI-202-2:(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone

The intermediate MDI-202-1 (33 mg, 0.05 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (23.3 mg, 0.06 mmol), Pd(dppf)Cl₂ (3.6 mg, 0.005 mmol)and potassium phosphate (31.3 mg, 0.15 mmol) were dissolved in1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced withnitrogen, which was repeated 3 times and the mixture was heated to 100°C., reacted overnight, and cooled to room temperature. Water was addedand the mixture was extracted with ethyl acetate twice. The organicphases were combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford intermediate MDI-202-2 with a yield of 85.0%.

¹H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8.0 Hz, 1H), 7.98 (d, J=4.0 Hz,2H), 7.49 (s, 1H), 7.20 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0Hz, 1H), 6.00 (s, 2H), 5.79 (s, 2H), 5.35 (s, 2H), 5.04-4.87 (m, 4H),4.01 (s, 3H), 3.91 (t, J=8.0 Hz, J=20.0 Hz, 2H), 3.67-3.61 (m, 4H), 2.58(d, J=8.0 Hz, 2H), 1.11-1.07 (m, 3H), 0.95-0.91 (m, 6H), 0.06 (s, 9H),0.03 (s, 9H), 0.02 (s, 9H).

Synthesis of compound MDI-202:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone

The intermediate MDI-202-2 (36.0 mg, 0.04 mmol) was dissolved inmethanol (4 ml), to which concentrated hydrochloric acid (2 ml) wasadded. The mixture was heated to 50° C., reacted for 6 hours, andconcentrated. The solid was dissolved with 1 ml methanol, to which 2 mlof concentrated aqueous ammonia was added. The mixture was concentratedto give a residue. The residue was dissolved in methanol and wasconcentrated to dryness, which was repeated 3 times. The resultingresidue was purified by a preparation plate to afford 5.0 mg of thefinal product with a yield of 25.4%.

¹H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 12.87 (s, 1H), 9.89 (s, 1H),8.35 (d, J=8.0 Hz, 2H), 7.94 (s, 1H), 7.42 (s, 1H), 7.15 (d, J=8.0 Hz,1H), 7.06 (d, J=12.0 Hz, 1H), 6.95 (d, J=12.0 Hz, 1H), 4.89 (s, 2H),4.67 (s, 2H), 3.92 (s, 3H), 2.51-2.48 (m, 2H), 1.05 (t, J=8.0 Hz, 3H).

Example 4:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)ketone (MDI-203)

MDI-203 may also be named as5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidin-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol.

Synthetic Route of MDI-203:

Synthesis Method:

Synthesis of Intermediate MDI-203-1:(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)ketone

1-methylpiperidine-4-carboxylic acid (18.6 mg, 0.13 mmol) andN,N-diisopropylethylamine (46.0 mg, 0.36 mmol) was dissolved in DMF, towhich HATU (67.8 mg, 0.18 mmol) was added. It was allowed to react atroom temperature for 10 minutes. Intermediate tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(80 mg, 0.12 mmol) was dissolved in 5 ml dichloromethane, to which 1 mlof trifluoroacetic acid was added. The reaction mixture was stirred atroom temperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and concentrated to dryness (toremove trifluoroacetic acid), which was repeated 3 times. Then theresulting residue was dissolved in DMF, which was slowly added to theprevious reaction solution. It was allowed to react at room temperatureovernight. Water was added to quench the reaction. The resulting mixturewas extracted twice with ethyl acetate and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-203-1 with a yield of 40.2%.

¹H NMR (400 MHz, CDCl3) δ8.29-8.22 (m, 1H), 7.76 (s, 1H), 7.41-7.26 (m,1H), 5.85 (s, 2H), 5.69 (s, 2H), 4.88-4.59 (m, 4H), 3.63-3.54 (m, 6H),3.21-2.81 (m, 5H), 2.28-2.01 (m, 4H), 0.93-0.83 (m, 5H), 0.03 (s, 9H),0.02 (s, 9H).

Synthesis of Intermediate MDI-203-2:(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)ketone

The intermediate MDI-203-1 (41.29 mg, 0.06 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(27.1 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol) and potassiumphosphate (36.2 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 ml) andwater (2 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added and the resultingmixture was extracted with ethyl acetate twice. The organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-203-2 with a yield of 40.9%.

¹H NMR (400 MHz, CDCl3) δ8.50-8.44 (m, 1H), 7.49 (s, 1H), 7.22 (dd,J=12.0 Hz, 2H), 7.04 (d, J=12.0 Hz, 1H), 5.98 (d, J=12.0 Hz, 2H), 5.78(s, 2H), 5.34 (s, 2H), 4.84-4.69 (m, 4H), 3.90-3.86 (m, 2H), 3.66-3.58(m, 4H), 3.38-3.30 (m, 2H), 2.61-2.54 (m, 5H), 2.13-2.05 (m, 4H),1.10-1.01 (m, 5H), 0.97-0.89 (m, 3H), 0.03 (s, 9H), 0.02 (s, 18H).

Synthesis of compound MDI-203:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)ketone

Intermediate MDI-203-2 (26.4 mg, 0.03 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml methanol, to which 2 ml concentrated ammoniawater was added. It was concentrated to give a residue. The residue wasdissolved in methanol and concentrated to dryness (to remove ammoniawater), which was repeated 3 times. After separation, 5.0 mg of thefinal product was obtained with a yield of 34.2%.

¹H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 9.87 (s, 1H), 9.24 (s, 1H),8.32 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.03 (d,J=12.0 Hz, 1H), 6.96 (d, J=12.0 Hz, 1H), 4.80 (s, 2H), 4.48 (s, 2H),3.04-3.01 (m, 2H), 2.79 (s, 3H), 2.55-2.51 (m, 2H), 2.05-1.99 (m, 3H),1.85-1.78 (m, 2H), 1.01-0.98 (m, 3H). The signals of the two H weremasked by the water peak (8=3.37).

Example 5:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone(MDI-204)

MDI-204 may also be named as5-ethyl-2-fluoro-4-{3-[5-(4-methylpiperazine-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol.

Synthetic Route of MDI-204:

Synthesis Method:

Synthesis of Intermediate MDI-204-1: (2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

5-(4-methylpiperazin-1-yl)pyrazine-2-carboxylic acid (28.9 mg, 0.13mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) were dissolvedin DMF, to which HATU (67.8 mg, 0.18 mmol) was added. It was allowed toreact at room temperature for 10 minutes. Intermediate tert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilylethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (80mg, 0.12 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml oftrifluoroacetic acid was added. The reaction mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and concentrated to dryness (toremove trifluoroacetic acid), which was repeated 3 times. Then theresulting residue was dissolved in DMF, which was slowly added to theprevious reaction solution. It was allowed to react at room temperatureovernight. Water was added to quench the reaction, and the resultingmixture was extracted twice with ethyl acetate. The organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-204-1 with a yield of 43%.

¹H NMR (400 MHz, CDCl3) δ8.86-8.84 (m, 1H), 8.41-8.33 (m, 1H), 8.07-8.05(m, 1H), 7.76 (d, J=4.0 Hz, 1H), 7.42-7.38 (m, 1H), 5.92 (s, 2H), 5.70(d, J=4.0 Hz, 2H), 5.23-4.88 (m, 4H), 3.77-3.65 (m, 4H), 3.61-3.55 (m,4H), 2.55 (t, J=4.0 Hz, 4H), 2.37 (s, 3H), 0.94-0.83 (m, 4H), 0.03 (s,9H), 0.02 (s, 9H).

Synthesis of Intermediate MDI-204-2:(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

The intermediate MDI-204-1 (46.0 mg, 0.06 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(27.1 mg, 0.07 mmol), Pd(dppf)Cl₂ (4.2 mg, 0.006 mmol) and potassiumphosphate (36.2 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 ml) andwater (2 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added and the resultingmixture was extracted with ethyl acetate twice. The organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-204-2 with a yield of 47.2%.

¹H NMR (400 MHz, CDCl3) δ8.86-8.84 (m, 1H), 8.51-8.43 (m, 1H), 8.08-8.06(m, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.26-7.23 (m, 1H), 7.21-7.14 (m, 1H),7.02 (d, J=8.0 Hz, 1H), 5.97 (s, 2H), 5.75 (d, J=4.0 Hz, 2H), 5.32 (s,2H), 5.25-5.16 (m, 2H), 4.99-4.90 (m, 2H), 3.87-3.83 (m, 2H), 3.77-3.74(m, 4H), 3.63-3.56 (m, 4H), 2.56-2.51 (m, 6H), 2.37 (s, 3H), 1.07-1.01(m, 3H), 0.99-0.88 (m, 6H), 0.03 (s, 9H), −0.07 (s, 9H), −0.09 (s, 9H).

Synthesis of Compound MDI-204:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

Intermediate MDI-204-2 (28.7 mg, 0.03 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Theresulting solid was dissolved in 1 ml methanol, to which 2 mlconcentrated ammonia water was added. It was concentrated to give aresidue. The residue was dissolved in methanol and concentrated todryness (to remove ammonia water), which was repeated 3 times. Afterseparation, 4.0 mg of the final product was obtained with a yield of23.51%.

¹H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.79 (d, J=16.0 Hz, 1H),9.85 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.34-8.30 (m, 1H), 7.40 (s,1H), 7.14-7.10 (m, 1H), 7.03 (d, J=12.0 Hz, 1H), 6.92 (d, J=12.0 Hz,1H), 5.08-4.65 (m, 4H), 2.55-2.49 (m, 6H), 2.24 (s, 3H), 2.03-1.97 (m,4H), 1.04-1.02 (m, 3H).

Example 6:(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone(MDI-205)

MDI-205 may also be named as3-ethyl-4-{3-[5-(4-methylpiperazine-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol.

Synthetic Route of MDI-205:

Synthesis Method:

Synthesis of Intermediate MDI-205-1: 4-benzyloxy-2-ethyl-iodobenzene

3-ethyl-4-iodophenol (200 mg, 0.81 mmol), benzyl bromide (165.5 mg, 0.97mmol) and potassium carbonate (222.9 mg, 1.61 mmol) were dissolved inDMF. It was allowed to react at room temperature for two hours. Waterwas added and the resulting mixture was extracted twice with EA. Theorganic phases were combined, washed with water, saturated brine, driedover anhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford 250 mg of colorless oily product with a yield of 91.7%.

¹H NMR (400 MHz, CDCl3) δ7.70 (d, J=8.0 Hz, 1H), 7.46-7.36 (m, 5H), 6.92(d, J=4.0 Hz, 1H), 6.57 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 5.06 (s, 2H), 2.72(dd, J=8.0 Hz, J=16.0 Hz, 2H), 1.22 (t, J=8.0 Hz, 3H).

Synthesis of Intermediate MDI-205-2: (2-(4-(phenoxy)-2-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

MDI-205-1 (250.0 mg, 0.74 mmol), pinacol borate (225.1 mg, 0.89 mmol),Pd(dppf)Cl₂ (54.0 mg, 0.07 mmol) and KOAc (217.6 mg, 2.22 mmol) weredissolved in 1,4-dioxane (10 ml). The atmosphere was replaced withnitrogen, which was repeated 3 times. The mixture was heated to 100° C.and reacted overnight. After the reaction was completed, it was quenchedwith water, extracted with ethyl acetate, and the organic phase waswashed with saturated sodium chloride solution, and dried over anhydroussodium sulfate. It was concentrated and separated by columnchromatography to afford a colorless oil with a yield of 70%.

¹H NMR (400 MHz, CDCl3) δ 7.77 (d, J=8.0 Hz, 1H), 7.47-7.34 (m, 5H),6.86-6.80 (m, 2H), 5.11 (s, 2H), 2.93 (dd, J=8.0 Hz, J=16.0 Hz, 2H),1.35 (s, 12H), 1.21 (t, J=8.0 Hz, 3H).

Synthesis of Compound MDI-205-3:(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

The intermediate 5-(4-methylpiperazin-1-yl)pyrazine-2 carboxylic acid(64.2 mg, 0.29 mmol) and N,N-diisopropylethylamine (93.2 mg, 0.72 mmol)were dissolved in DMF, to which HATU (109.7 mg, 0.29 mmol) was added. Itwas allowed to react at room temperature for 10 minutes. Intermediatetert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilylethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(160.0 mg, 0.24 mmol) was dissolved in 5 ml dichloromethane, to which 1ml of trifluoroacetic acid was added. The reaction mixture was stirredat room temperature for 30 minutes, and concentrated to give a residue.The residue was dissolved in dichloromethane and concentrated to dryness(to remove trifluoroacetic acid), which was repeated 3 times. Then theresulting residue was dissolved in DMF, which was slowly added to theprevious reaction solution. It was allowed to react at room temperatureovernight. Water was added to quench the reaction, and the resultingmixture was extracted twice with ethyl acetate. The organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-205-3 with a yield of 49.2%.

¹H NMR (400 MHz, CDCl3) δ 8.88 (dd, J=8.0 Hz, J=4.0 Hz 1H), 8.42 (dd,J=8.0 Hz, J=20.0 Hz 1H), 8.10 (dd, J=8.0 Hz, J=4.0 Hz 1H), 7.80 (s, 1H),7.41-7.46 (m, 1H), 5.96 (s, 2H), 5.74 (d, J=4.0 Hz, 2H), 5.27 (s, 1H),5.19 (s, 1H), 4.99 (s, 1H), 4.91 (s, 1H), 3.80-3.78 (m, 4H), 3.63-3.59(m, 4H), 2.59-2.56 (m, 4H), 2.40 (s, 3H), 0.97-0.91 (m, 4H), 0.03 (s,9H), 0.02 (s, 9H).

Synthesis of Compound MDI-205-4:(2-(6-(4-(phenoxy)-2-ethyl-phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

Intermediate MDI-205-3 (91.0 mg, 0.12 mmol), intermediate MDI-205-2(48.1 mg, 0.14 mmol), Pd(PPh3)4 (13.6 mg, 0.01 mmol) and potassiumphosphate (75.4 mg, 0.36 mmol) were dissolved in 1,4-dioxane (20 ml) andwater (4 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added, and the resultingmixture was extracted 2 times with ethyl acetate. The organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford intermediate MDI-205-4 with a yield of 44.1%.

¹H NMR (400 MHz, CDCl3) δ 8.88 (dd, J=8.0 Hz, J=4.0 Hz 1H), 8.46 (dd,J=4.0 Hz, J=8.0 Hz 1H), 8.11 (dd, J=8.0 Hz, J=4.0 Hz 1H), 7.52-7.31 (m,6H), 7.27-7.22 (m, 2H), 7.00 (d, J=4.0 Hz, 1H), 6.91 (dd, J=4.0 Hz,J=8.0 Hz, 1H), 6.00 (s, 2H), 5.77 (d, J=4.0 Hz, 2H), 5.20 (s, 1H), 5.19(s, 1H), 5.15 (s, 2H), 5.01 (s, 1H), 4.93 (s, 1H), 3.81-3.77 (m, 4H),3.65-3.61 (m, 4H), 2.62-2.57 (m, 6H), 2.40 (s, 3H), 1.10 (t, J=8.0 Hz,3H), 0.95-0.91 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

Synthesis of Compound MDI-205-5:(2-(6-(2-ethyl-4-hydroxyphenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

Intermediate MDI-205-4 (47.0 mg, 0.05 mmol) was dissolved in 10 mlmethanol, to which 5 mg 10% Pd/C was added. The atmosphere was replacedwith hydrogen, which was repeated three times. It was allowed to reactat room temperature overnight. The palladium on carbon was filtered offand the filtrate was concentrated to afford intermediate MDI-205-5 witha yield of 78.0%, which was directly used in the next step.

Synthesis of Compound MDI-205:(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

The intermediate MDI-205-5 (33.0 mg, 0.04 mmol) was dissolved in 4 MLmethanol, to which 2 ml concentrated hydrochloric acid was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated togive a residue. The residue was dissolved in methanol and wasconcentrated to dryness (to remove hydrochloric acid), which wasrepeated 3 times. The resulting product was dissolved 1 ml methanol and2 ml aqueous ammonia was added for neutralization, and the resultingmixture was concentrated to give a residue. The residue was dissolved inmethanol and was concentrated to dryness (to remove aqueous ammonia),which was repeated 2 times. The obtained product was purified by apreparation plate to afford 6.2 mg of the product with a yield of 27.7%.

¹H NMR (400 MHz, MeOD-d4) δ 8.72 (d, J=4.0 Hz, 1H), 8.28 (dd, J=4.0 Hz,J=8.0 Hz, 2H), 7.40 (s, 1H), 7.18 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.09 (d,J=8.0 Hz, 1H), 6.80 (d, J=4.0 Hz, 1H), 6.72-6.69 (m, 1H), 5.17 (s, 2H),4.85 (s, 2H), 3.83-3.81 (m, 4H), 2.67-2.64 (m, 4H), 2.60 (dd, J=4.0 Hz,J=8.0 Hz, 2H), 2.43 (s, 3H), 1.10 (t, J=8.0 Hz, 3H).

Example 7: 5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-206)

Synthetic Route of MDI-206:

Synthesis Method:

Synthesis of Intermediate MDI-206-1:(6-bromo-3-(5-(benzenesulfonyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4, 5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

Tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane, to which 1 mlof trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue (toremove trifluoroacetic acid). The residue was dissolved indichloromethane and was concentrated to dryness, which was repeated 3times. The resulting residue was dissolved in 5 ML DCM and Et₃N (0.08ml, 0.59 mmol), cooled to 0° C., and benzenesulfonyl chloride (28.6 mg,0.16 mmol) was slowly added. It was allowed to react at room temperaturefor 2 hours, and water was added to quench the reaction. The resultingmixture was extracted twice with DCM, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-206-1 with a yield of 41.4%.

¹H NMR (400 MHz, CDCl3) δ 8.32 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz,2H), 7.77 (s, 1H), 7.62-7.55 (m, 3H), 7.42 (d, J=8.0 Hz, 1H), 5.85 (s,2H), 5.70 (s, 2H), 4.66-4.58 (m, 4H), 3.59-3.51 (m, 4H), 0.94-0.87 (m,4H), 0.03 (s, 18H).

Synthesis of Intermediate MDI-206-2:(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)-3-(5-benzenesulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

The intermediate MDI-206-1 (53.0 mg, 0.08 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(35.8 mg, 0.09 mmol), Pd(dppf)Cl₂ (5.5 mg, 0.008 mmol) and potassiumphosphate (47.9 mg, 0.23 mmol) were dissolved in 1,4-dioxane (10 ml) andwater (2 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added and the resultingmixture was extracted with ethyl acetate twice and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified on a silica gelcolumn to afford intermediate MDI-206-2 with a yield of 74.3%.

¹H NMR (400 MHz, CDCl3) δ 8.42 (d, J=8.0 Hz, 1H), 7.96-7.94 (m, 2H),7.62-7.57 (m, 3H), 7.46 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 7.04 (d, J=12.0 Hz, 1H), 5.89 (s, 2H), 5.75 (s, 2H), 5.34 (s,2H), 4.67-4.60 (m, 4H), 3.90-3.86 (m, 2H), 3.62-3.51 (m, 4H), 2.58 (dd,J=8.0 Hz, J=16.0 Hz, 2H), 1.09-1.05 (m, 3H), 0.93-0.88 (m, 6H), 0.06 (s,9H), 0.03 (s, 9H), 0.02 (s, 9H).

Synthesis of Compound MDI-206:5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

Intermediate MDI-206-2 (50.0 mg, 0.06 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Theresulting solid was dissolved in 1 ml methanol, and pH was adjusted withsodium bicarbonate solution to 8-9. The resulting mixture was extracted4 times with dichloromethane, and the organic phases were combined,dried over anhydrous sodium sulfate, and purified by a preparation plateto afford 13 mg of the final product with a yield of 46.2%.

¹H NMR (400 MHz, MeOD-d4) δ 8.22 (d, J=8.0 Hz, 1H), 7.98-7.96 (m, 2H),7.69-7.65 (m, 3H), 7.41 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.96-6.89 (m,2H), 4.61-4.52 (m, 4H), 2.57 (dd, J=16.0 Hz, J=8.0 Hz, 2H), 1.08 (t,J=8.0 Hz, 3H).

Example 8:5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol(MDI-207)

Synthetic Route of MDI-207:

Synthesis Method:

Synthesis of Intermediate MDI-207-1:(6-bromo-3-(5-(pyrazin-2ylmethyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol

Tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(47.0 mg, 0.07 mmol) was dissolved in 5 ml dichloromethane, to which 1ml of trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes. Water was added and saturated sodiumbicarbonate solution was used to adjust pH=9. The resulting mixture wasextracted with DCM. The organic phase was washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentrated.The resulting solid was dissolved in 1,2-dichloroethane, to which2-pyrazinecarboxaldehyde (30.6 mg, 0.28 mmol) was added. The mixture wasstirred at room temperature for 1 hour, to which sodiumtriacetylborohydride (60.0 mg, 0.28 mmol) was added. It was allowed toreact at room temperature for 4 hours, and water was added to quench thereaction. The resulting mixture was extracted with DCM twice, and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford the product MDI-207-1 with a yield of 49.5%.

¹H NMR (400 MHz, CDCl3) δ 8.81 (d, J=4.0 Hz, 1H), 8.60 (dd, J=8.0 Hz,J=4.0 Hz, 1H), 8.54 (d, J=4.0 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H), 7.77 (d,J=4.0 Hz, 1H), 7.41 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 5.88 (s, 2H), 5.72 (s,2H), 4.28 (s, 2H), 4.12 (dd, J=4.0 Hz, J=12.0 Hz, 4H), 3.62-3.55 (m,4H), 0.96-0.87 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

Synthesis of Intermediate MDI-207-2:(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-(5-(pyrazin-2ylmethyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

The intermediate MDI-207-1 (20.0 mg, 0.03 mmol), the intermediate(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (14.5 mg, 0.04 mmol), Pd(dppf)Cl₂ (2.3 mg, 0.003 mmol)and potassium phosphate (19.4 mg, 0.09 mmol) were dissolved in1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced withnitrogen, which was repeated 3 times. The mixture was heated to 100° C.,reacted overnight, and cooled to room temperature. Water was added andthe resulting mixture was extracted with ethyl acetate twice, theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford intermediate MDI-207-2 with a yield of93.0%.

¹H NMR (400 MHz, CDCl3) δ 8.82 (d, J=4.0 Hz, 1H), 8.60 (dd, J=8.0 Hz,J=4.0 Hz, 1H), 8.54 (d, J=4.0 Hz, 1H), 8.48 (d, J=8.0 Hz, 1H), 7.47 (d,J=4.0 Hz, 1H), 7.23 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.19 (d, J=8.0 Hz,1H), 7.05 (d, J=12.0 Hz, 1H), 5.92 (s, 2H), 5.77 (s, 2H), 5.34 (s, 2H),4.30 (s, 2H), 4.13 (dd, J=4.0 Hz, J=12.0 Hz, 4H), 3.88-3.86 (m, 2H),3.63-3.58 (m, 4H), 2.57 (d, J=8.0 Hz, 2H), 1.07 (t, J=8.0 Hz, 3H),0.92-0.90 (m, 6H), 0.06 (s, 9H), 0.03 (s, 9H), 0.02 (s, 9H).

Synthesis of compound MDI-207:5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

The intermediate MDI-207-2 (24.0 mg, 0.03 mmol) was dissolved in 4 MLmethanol, to which 2 ml concentrated hydrochloric acid was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated togive a residue. The residue was dissolved in methanol and wasconcentrated to dryness, which was repeated 3 times. The resultingproduct was dissolved 1 ml methanol and 2 ml aqueous ammonia was addedfor neutralization, and the resulting mixture was concentrated to give aresidue. The residue was dissolved in methanol and was concentrated todryness, which was repeated 2 times. The obtained product was purifiedby a preparation plate to afford 8 mg of the product with a yield of61.8%.

¹H NMR (400 MHz, MeOD-d4) δ 8.80 (d, J=4.0 Hz, 1H), 8.65 (dd, J=4.0 Hz,J=4.0 Hz, 1H), 8.56 (d, J=4.0 Hz, 1H), 8.26 (dd, J=4.0 Hz, J=4.0 Hz,1H), 7.41 (d, J=4.0 Hz, 1H), 7.17 (dd, J=12.0 Hz, J=4.0 Hz, 1H),6.91-6.89 (m, 2H), 4.30 (s, 2H), 4.07 (s, 4H), 2.56 (dd, J=8.0 Hz,J=16.0 Hz, 2H), 1.07 (t, J=8.0 Hz, 3H).

Example 9:4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol(MDI-208)

Synthetic Route of MDI-208:

Synthesis of IntermediateMDI-208-1:(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylateTert-butyl

Tert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(500.0 mg, 0.75 mmol),2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboran(401.9 mg, 1.13 mmol), Pd(PPh₃)₄(86.9 mg, 0.08 mmol) and potassiumphosphate (478.9 mg, 2.26 mmol) were dissolved in 1,4-dioxane (30 ml)and water (6 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added and the resultingmixture was exacted twice with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified on a silica gelcolumn to afford intermediate MDI-208-1 with a yield of 85.1%.

¹H NMR (400 MHz, CDCl3) δ 8.50-8.45 (m, 1H), 7.53-7.37 (m, 6H), 7.26 (d,J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.99 (d, J=12.0 Hz, 1H), 5.97 (d,J=8.0 Hz, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.67-4.54 (m, 4H), 3.65-3.59(m, 4H), 2.55 (d, J=8.0 Hz, 2H), 1.57 (s, 9H), 1.05 (t, J=8.0 Hz, 3H),0.95-0.89 (m, 4H), 0.02 (s, 9H), 0.01 (s, 9H).

Synthesis of intermediate MDI-208-2:(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-3-(5-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

Tert-butyl2-(6-(4-(phenoxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(80.0 mg, 0.10 mmol) was dissolved in 5 ml dichloromethane, to which 1ml trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes. Water was added and saturated sodiumbicarbonate solution was used to adjust pH=9. The resulting mixture wasextracted with DCM, and the organic phase was washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentrated.The obtained solid was dissolved in 2 ml DMF, and Et₃N (0.1 ml) andbromomethylcyclopropane (27.0 mg, 0.20 mmol) were added. The mixture washeated to 60° C., reacted overnight, and cooled to room temperature.Water was added and the resulting mixture was extracted with EA, washedwith water and saturated brine, dried over anhydrous sodium sulfate,concentrated, and purified by silica gel column to afford MDI-208-2 witha yield of 33.5%.

¹H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8.0 Hz, 1H), 7.53-7.37 (m, 6H),7.23 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.06 (dd, J=12.0 Hz, J=4.0 Hz, 1H),6.98 (d, J=8.0 Hz, 1H), 5.94 (d, J=4.0 Hz, 2H), 5.76 (s, 2H), 5.23 (s,2H), 4.13 (d, J=36.0 Hz, 4H), 3.67-3.58 (m, 4H), 2.80 (d, J=8.0 Hz, 2H),2.55 (dd, J=12.0 Hz, J=8.0 Hz, 2H), 2.32-2.22 (m, 1H), 1.06 (t, J=8.0Hz, 3H), 0.92-0.90 (m, 4H), 0.63 (d, J=8.0 Hz, 2H), 0.27 (d, J=4.0 Hz,2H), 0.03 (s, 9H), 0.02 (s, 9H).

Synthesis of Compound MDI-208:4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

Intermediate MDI-208-2 (28.0 mg, 0.04 mmol) was dissolved in 10 mlmethanol, to which 5 mg 10% Pd/C was added. The atmosphere was replacedwith hydrogen, which was repeated three times. The mixture was heated to40° C. and reacted overnight, filtered to remove palladium on carbon,and concentrated. The resulting solid was dissolved in 4 ml methanol, towhich 2 ml concentrated hydrochloric acid was added. The mixture washeated to 50° C., reacted for 6 hours and concentrated to give aresidue. The residue was dissolved in methanol and concentrated todryness, which was repeated 3 times. The resulting product was dissolved1 ml methanol and 2 ml aqueous ammonia was added for neutralization, andthe resulting mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness (to removeaqueous ammonia), which was repeated 2 times. The obtained product waspurified by a preparation plate to afford 2 mg of the product with ayield of 13.1%.

¹H NMR (400 MHz, MeOD-d4) δ 8.27 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.42 (s,1H), 7.17 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.97-6.89 (m, 2H), 4.02 (s, 4H),2.80 (d, J=8.0 Hz, 2H), 2.59-2.53 (m, 2H), 1.10 (m, 4H), 0.66-0.61 (m,2H), 0.30-0.27 (m, 2H).

Example 10: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone (MDI-209)

Synthetic Route of MDI-209:

Synthesis Method:

Synthesis of Intermediate MDI-209-1:(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(cyclopropyl)ketone

The intermediate tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1ml of trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and was concentrated todryness, which was repeated 3 times. The resulting residue was dissolvedin 5 ml of DCM, to which triethylamine (24.3 mg, 0.24 mmol) was added.The temperature was lowered to 0° C., and cyclopropylformyl chloride(18.8 mg, 0.18 mmol) was slowly added dropwise. After the dropwiseaddition was completed, the reaction was warmed up to room temperatureand was allowed to react for 1-2 h. Water was added to quench thereaction and liquids were separated. The organic phase was dried oversodium sulfate and concentrated by column chromatography to affordcompound MDI-209-1 with a yield of 45%.

¹H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=17.8 Hz, J=8.6 Hz, 1H), 7.80-7.79(m, 1H), 7.41 (d, J=8.6 Hz, 1H), 5.97-5.92 (m, 2H), 5.71 (d, J=2.4 Hz,2H), 4.96-4.66 (m, 4H), 3.62-3.54 (m, 4H), 1.78-1.67 (m, 1H), 1.10-1.07(m, 2H), 0.94-0.84 (m, 6H), −0.05 (s, 9H), −0.08 (s, 9H).

Synthesis of intermediate MDI-209-2:cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone

The intermediate MDI-209-1 (50.5 mg, 0.08 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (34.8 mg, 0.1 mmol), Pd(dppf)Cl₂ (5.9 mg, 0.008 mmol)and potassium phosphate (50.9 mg, 0.24 mmol) were dissolved in1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced withnitrogen, which was repeated 3 times. The mixture was heated to 100° C.,reacted overnight, and cooled to room temperature. Water was added andthe resulting mixture was extracted twice with ethyl acetate and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purify by silicagel column to afford intermediate MDI-209-2 with a yield of 76.1%.

¹H NMR (400 MHz, CDCl3) δ 8.50-8.43 (m, 1H), 7.46-7.45 (m, 1H),7.25-7.22 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.02 (d, J=12.0 Hz, 1H),5.99-5.94 (m, 2H), 5.76 (s, 2H), 5.32 (s, 2H), 4.98-4.67 (m, 4H),3.88-3.84 (m, 2H), 3.64-3.55 (m, 4H), 2.57-2.51 (m, 2H), 1.79-1.68 (m,1H), 1.07-1.02 (m, 6H), 0.95-0.87 (m, 5H), 0.03 (s, 9H), −0.06-0.08 (m,18H).

Synthesis of compound MDI-209: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone

The intermediate MDI-209-2 (50 mg, 0.06 mmol) was dissolved in methanol(4 ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml methanol, to which 2 ml concentrated aqueousammonia was added. The mixture was concentrated to give a residue. Theresidue was dissolved in methanol and was concentrated to dryness, whichwas repeated 3 times. The resulting residue was purified by apreparation plate to afford 10.0 mg of the final product with a yield of38.1%.

¹H NMR (400 MHz, MeOD-d4) δ8.28 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.18(dd, J=8.4 Hz, J=1.4 Hz, 1H), 6.98 (d, J=12.0 Hz, 1H), 6.92 (d, J=12.0Hz, 1H), 4.95 (s, 2H), 4.65 (s, 2H), 2.59-2.53 (m, 2H), 1.98-1.89 (m,1H), 1.08 (t, J=8.0 Hz, 3H), 1.02-1.00 (m, 2H), 0.98-0.92 (m, 2H).

Example 11:4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol(MDI-210)

Synthetic Route of MDI-210:

Synthesis Method:

Synthesis of intermediate MDI-210-1:(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-3-(5-(cyclobutylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

Tert-butyl2-(6-(4-(phenoxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(80.0 mg, 0.10 mmol) was dissolved in 5 ml dichloromethane, to which 1ml trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes. Water was added and saturated sodiumbicarbonate solution was used to adjust pH=9. The resulting mixture wasextracted with DCM, washed with water and saturated brine, dried oversodium sulfate and concentrated. The obtained solid was dissolved in 3ml DMF, followed by addition of DIPEA (126.8 mg, 0.98 mmol) andbromomethylcyclobutane (29.3 mg, 0.20 mmol). The mixture was heated to60° C., reacted overnight, and cooled to room temperature. Water wasadded and the resulting mixture was extracted with EA, washed with waterand saturated brine, dried over anhydrous sodium sulfate, concentrated,and purified by silica gel column to afford MDI-210-1 with a yield of35.1%.

¹H NMR (400 MHz, CDCl3) δ 8.47 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.53-7.51(m, 2H), 7.46-7.37 (m, 4H), 7.23 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.06 (d,J=12.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 5.91 (s, 2H), 5.76 (s, 2H), 5.22(s, 2H), 4.02 (s, 2H), 3.94 (s, 2H), 3.65-3.56 (m, 4H), 2.93 (d, J=8.0Hz, 2H), 2.68-2.64 (m, 1H), 2.57 (dd, J=16.0 Hz, J=8.0 Hz, 2H),2.21-2.14 (m, 2H), 1.97-1.67 (m, 4H), 1.06 (t, J=8.0 Hz, 3H), 0.94-0.89(m, 4H), 0.02 (s, 18H).

Synthesis of Compound MDI-210:4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

Intermediate MDI-210-1 (35.0 mg, 0.05 mmol) was dissolved in 10 mlmethanol, to which 5 mg 10% Pd/C was added. The atmosphere was replacedwith hydrogen, which was repeated three times. The mixture was heated to40° C. and reacted overnight, filtered to remove palladium on carbon,and concentrated. The resulting solid was dissolved in 4 ml methanol, towhich 2 ml concentrated hydrochloric acid was added. The mixture washeated to 50° C., reacted for 6 hours and concentrated to give aresidue. The residue was dissolved in methanol and was concentrated todryness, which was repeated 3 times. The resulting product was dissolved1 ml methanol and 2 ml concentrated aqueous ammonia was added forneutralization, and the resulting mixture was concentrated to give aresidue. The residue was dissolved in methanol and was concentrated todryness, which was repeated 2 times. The obtained product was purifiedby a preparation plate to afford 4 mg of the product with a yield of20.7%.

¹H NMR (400 MHz, MeOD-d4) δ 8.27 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.42 (s,1H), 7.17 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.97-6.89 (m, 2H), 3.98 (s, 4H),3.00 (d, J=8.0 Hz, 2H), 2.72-2.68 (m, 1H), 2.59-2.53 (m, 2H), 2.21-2.18(m, 2H), 1.89-1.85 (m, 4H), 1.07 (t, J=8.0 Hz, 3H).

Example 12: cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone (MDI-211)

Synthetic Route of MDI-211:

Synthesis Method:

Synthesis of Intermediate MDI-211-1:(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)(cyclobutyl)ketone

The intermediate tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1ml of trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and was concentrated todryness, which was repeated 3 times. The resulting residue was dissolvedin 5 ml of DCM, to which triethylamine (24.3 mg, 0.24 mmol) was added.The temperature was reduced to 0° C. and cyclobutyl carbonyl chloride(21.3 mg, 0.18 mmol) was slowly added dropwise. After the dropwiseaddition was completed, the reaction was warmed up to room temperatureand was allowed to react for 1-2 h. Water was added to quench thereaction and liquids were separated. The organic phase was dried oversodium sulfate and concentrated by column chromatography to affordcompound MDI-211-1 with a yield of 43%.

¹H NMR (400 MHz, CDCl3) δ 8.39-8.31 (m, 1H), 7.77-7.76 (m, 1H),7.42-7.38 (m, 1H), 5.92-5.89 (m, 2H), 5.71-5.70 (m, 2H), 4.73-4.57 (m,4H), 3.60-3.54 (m, 4H), 3.37-3.27 (m, 1H), 2.46-2.39 (m, 2H), 2.34-2.20(m, 3H), 2.10-1.93 (m, 3H), 0.93-0.88 (m, 4H), −0.05 (s, 9H), −0.09 (s,9H).

Synthesis of Intermediate MDI-211-2: cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone

The intermediate MDI-211-1 (51.6 mg, 0.08 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(34.8 mg, 0. 1 mmol), Pd(dppf)Cl₂ (5.9 mg, 0.008 mmol) and potassiumphosphate (50.9 mg, 0.24 mmol) were dissolved in 1,4-dioxane (10 ml) andwater (2 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added and the resultingmixture was extracted twice with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford intermediate MDI-211-2 with a yield of 75.2%.

¹H NMR (400 MHz, CDCl3) δ 8.49-8.42 (m, 1H), 7.47-7.45 (m, 1H),7.25-7.22 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.02 (d, J=12.0 Hz, 1H),5.96-5.93 (m, 2H), 5.75 (s, 2H), 5.32 (s, 2H), 4.75-4.58 (m, 4H),3.88-3.83 (m, 2H)), 3.63-3.55 (m, 4H), 3.38-3.28 (m, 1H), 2.57-2.51 (m,2H), 2.48-2.20 (m, 4H), 2.06-2.00 (m, 1H), 1.96-1.92 (m, 1H), 1.08-1.05(m, 3H), 0.93-0.85 (m, 6H), 0.03 (s, 9H), −0.06-0.08 (m, 18H).

Synthesis of compound MDI-211: cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone

The intermediate MDI-211-2 (45 mg, 0.054 mmol) was dissolved in methanol(4 ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml methanol, 2 ml of concentrated aqueousammonia was added, and the mixture was concentrated to give a residue.The residue was dissolved in methanol and was concentrated to dryness,which was repeated 3 times. The resulting residue was separated by apreparation plate to afford 8.2 mg of the final product with a yield of34.2%.

¹H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.17(dd, J=8.4, 1.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.68-4.63(m, 4H), 3.54-3.46 (m, 1H), 2.57-2.53 (m, 2H), 2.43-2.26 (m, 4H),2.16-2.04 (m, 1H), 1.98-1.89 (m, 1H), 1.08 (t, J=8.0 Hz, 3H).

Example 13:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxylcyclobutyl)ketone(MDI-213)

Synthetic Route of MDI-213:

Synthesis Method:

Synthesis of Intermediate MDI-213-1:(3-(benzyloxy)cyclobutyl)(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)ketone

The intermediate 3-benzyloxy-cyclobutanecarboxylic acid (44.6 mg, 0.22mmol) and N,N-diisopropylethylamine (69.9 mg, 0.54 mmol) were dissolvedin DMF, to which HATU (82.3 mg, 0.22 mmol) was added. The mixture wasreacted at room temperature for 10 minutes. Intermediate tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(120.0 mg, 0.18 mmol) was dissolved in 5 ml dichloromethane, to which 1ml of trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and was concentrated todryness, which was repeated 3 times. The resulting residue was dissolvedin DMF, and then slowly added to the previous reaction solution. It wasallowed to react at room temperature overnight, and water was added toquench the reaction. The resulting mixture was extracted twice withethyl acetate, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, concentrated,and purified by silica gel column to afford intermediate MDI-213-1 witha yield of 35.3%.

¹H NMR (400 MHz, CDCl3) δ 8.41 (dd, J=8.0 Hz, J=20.0 Hz, 1H), 7.80-7.78(m, 1H), 7.43-7.31 (m, 6H), 5.94 (d, J=12.0 Hz, 2H), 5.73 (d, J=4.0 Hz,2H), 4.76-4.61 (m, 4H), 4.49 (s, 2H), 4.10-4.04 (m, 1H), 3.63-3.57 (m,4H)), 2.80-2.78 (m, 1H), 2.58-2.53 (m, 2H), 2.46-2.41 (m, 2H), 0.96-0.90(m, 4H), 0.02 (s, 9H), −0.03 (s, 9H).

Synthesis of Intermediate MDI-213-2:(3-(benzyloxy)cyclobutyl)(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone

Intermediate MDI-213-1 (48.0 mg, 0.06 mmol), intermediate MDI-10-2 (30.4mg, 0.08 mmol), Pd(dppf)Cl2 (4.7 mg, 0.01 mmol) and potassium phosphate(40.6 mg, 0.19 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4ml). The atmosphere was replaced with nitrogen, which was repeated 3times. The mixture was heated to 100° C., reacted overnight, and cooledto room temperature. Water was added, and the resulting mixture wasextracted 2 times with ethyl acetate, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-213-2 with a yield of 71.5%.

¹H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.49-7.48(m, 1H), 7.38-7.32 (m, 5H), 7.28-7.24 (m, 1H), 7.19 (d, J=8.0 Hz, 1H),7.05 (d, J=12.0 Hz, 1H), 5.99 (d, J=12.0 Hz, 2H), 5.78 (d, J=4.0 Hz,2H), 5.34 (s, 2H), 4.78-4.62 (m, 4H), 4.50 (s, 2H), 4.12-4.05 (m, 1H),3.90-3.86 (m, 2H), 3.66-3.58 (m, 4H), 2.80-2.78 (m, 1H), 2.59-2.54 (m,4H), 2.46-2.44 (m, 2H), 1.10-1.05 (m, 3H), 0.95-0.90 (m, 6H), 0.06 (s,9H), −0.04 (s, 18H).

Synthesis of Intermediate MDI-213-3:(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxylcyclobutyl)ketone

Intermediate MDI-213-2 (43.0 mg, 0.05 mmol) was dissolved in 10 mlmethanol, and 5 mg of 10% Pd/C was added. The atmosphere was replacedwith hydrogen, which was repeated three times. The mixture was reactedovernight at room temperature, filtered off palladium carbon, andconcentrated to afford intermediate MDI-213-3, which was directly usedin the next step.

Synthesis of compound MDI-213:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxylcyclobutyl)ketone

The intermediate MDI-213-3 (36.1 mg, 0.05 mmol) was dissolved in 4 MLmethanol and 2 ml concentrated hydrochloric acid was added. The mixturewas heated to 50° C., reacted for 6 hours, and concentrated to give aresidue. The residue was dissolved in methanol and was concentrated todryness, which was repeated 3 times. The resulting product was dissolved1 ml methanol and 2 ml aqueous ammonia was added for neutralization, andthe resulting mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 2 times. The obtained product was purified by a preparationplate to afford 4 mg of the product with a yield of 16.4%.

¹H NMR (400 MHz, MeOD-d4) δ 8.28 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.43-7.42(m, 1H), 7.19 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.97-6.89 (m, 2H), 4.72-4.62(m, 4H), 4.23-4.20 (m, 1H), 2.95-2.91 (m, 1H), 2.63-2.53 (m, 4H),2.26-2.18 (m, 2H), 1.10 (t, J=8.0 Hz, 3H).

Example 14:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone(MDI-214)

Synthetic Route of MDI-214:

Synthesis Method:

Synthesis of Intermediate MDI-214-1:(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone

Tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(45 mg, 0.06 mmol) was dissolve in 5 ml of dichloromethane, to which 1ml of trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and was concentrated todryness, which was repeated 3 times. The resulting residue was dissolvedin 5 ml of DMF, followed by addition of pyridazine-4-carboxylic acid (9mg, 0.07 mmol), HATU (32 mg, 0.08 mmol) and DIPEA (0.05 ml, 0.30 mmol).It was allowed to react at room temperature for 16 hours and water wasadded to quench the reaction. The mixture was extracted twice with EA,and the organic phases were combined, washed with water and saturatedbrine, dried over anhydrous sodium sulfate, concentrated, and purifiedby silica gel column to afford 23 mg of intermediate MDI-214-1 with ayield of 51.2%.

¹H NMR (400 MHz, CDCl3) δ 9.45-9.50 (m, 2H), 8.34 (dd, J=38.3 Hz, J=8.6Hz, 1H), 7.79 (t, J=1.9 Hz, 1H), 7.69-7.66 (m, 1H), 7.45-7.41 (m, 1H),5.92 (d, J=31.9 Hz, 2H), 5.72 (d, J=5.3 Hz, 2H), 4.95-4.93 (m, 2H),4.68-4.66 (m, 2H), 3.65-3.54 (m, 4H), 1.08-0.77 (m, 4H), 0.05-0.13 (m,18H).

Synthesis of Intermediate MDI-214-2:(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone

The intermediate MDI-214-1 (23 mg, 0.03 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(20 mg, 0.05 mmol), Pd(dppf)Cl₂ (3 mg, 0.003 mmol) and potassiumphosphate (22 mg, 0.10 mmol) were dissolved in 1,4-dioxane (5 ml) andwater (1 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted for 16 h,and cooled to room temperature. Water was added and the resultingmixture was extracted 2 times with ethyl acetate and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford 25 mg of intermediate MDI-214-2 with a yield of 84.7%.

¹H NMR (400 MHz, CDCl3) δ 9.46-9.42 (m, 2H), 8.62-8.31 (m, 1H),7.71-7.67 (m, 1H), 7.51-7.47 (m, 1H), 7.25 (dd, J=8.4, 1.3 Hz, 1H), 7.18(dd, J=8.4, 4.0 Hz, 1H), 7.03 (dd, J=11.6, 6.0 Hz, 1H), 5.96 (d, J=31.6Hz, 2H), 5.78 (d, J=5.2 Hz, 2H), 5.34 (d, J=2.7 Hz, 2H), 5.02-4.95 (m,2H), 4.71-4.67 (m, 2H), 3.90-3.86 (m, 2H), 3.66-3.62 (m, 4H), 2.57-2.54(m, 2H), 1.14-0.81 (m, 9H), 0.06 (d, J=2.1 Hz, 9H), −0.04 (dd, J=12.1Hz, J=8.6 Hz, 18H).

Synthesis of Compound MDI-214:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone

Intermediate MDI-214-2 (25 mg, 0.03 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated togive a residue. The residue was dissolved in methanol and wasconcentrated to dryness, which was repeated 3 times. The resultingresidue was dissolve in methanol, 1 ml of aqueous ammonia was added, andthen the mixture was concentrated, and purified by a preparation plateto afford 4 mg of the final product with a yield of 29.4%.

¹H NMR (400 MHz, MeOD-d4) δ 9.48 (dd, J=2.3, J=1.3 Hz, 1H), 9.42 (dd,J=5.2, J=1.3 Hz, 1H), 8.26 (s, 1H), 8.02 (dd, J=5.3, J=2.2 Hz, 1H), 7.43(d, J=1.1 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 6.93 (dd, J=19.7, J=10.4 Hz,2H), 4.90 (s, 2H), 4.73 (s, 2H), 2.55 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5Hz, 3H).

Example 15:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone(MDI-215)

Synthetic Route of MDI-215:

Synthesis Method:

Synthesis of Intermediate MDI-215-1:(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone

Tert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (200mg, 0.30 mmol) was dissolved in 10 ml dichloromethane, and 2 ml oftrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and was concentrated todryness, which was repeated 3 times. The resulting residue was dissolvedin 10 ml of DMF, followed by addition of pyridazine-3-carboxylic acid(45 mg, 0.36 mml), HATU (164 mg, 0.43 mmol) and DIPEA (0.18 ml, 1.08mmol). It was allowed to react at room temperature for 16 hours andwater was added to quench the reaction. The resulting mixture wasextracted twice with EA, and the organic phases were combined, washedwith water and saturated brine, dried over anhydrous sodium sulfate,concentrated and purified by silica gel column to afford 98 mg ofintermediate MDI-215-1 with a yield of 49.2%.

¹H NMR (400 MHz, CDCl3) δ 9.35-9.30 (m, 1H), 8.40 (dd, J=19.4 Hz, J=8.6Hz, 1H), 8.25 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.79 (dd, J=3.1, J=1.5 Hz,1H), 7.72-7.68 (m, 1H), 7.46-7.43 (m, 1H), 5.95 (d, J=21.7 Hz, 2H), 5.73(d, J=3.2 Hz, 2H), 5.40-5.24 (m, 2H), 5.06-4.98 (m, 2H), 3.66-3.56 (m,4H), 0.98-0.87 (m, 4H), 0.00-0.05 (m, 9H), −0.09 (s, 9H).

Synthesis of Intermediate MDI-215-2:(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone

The intermediate MDI-215-1 (98 mg, 0.15 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(100 mg, 0.25 mmol), Pd(dppf)Cl₂ (15 mg, 0.015 mmol) and potassiumphosphate (110 mg, 0.50 mmol) were dissolved in 1,4-dioxane (25 ml) andwater (5 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted for 16 h,and cooled to room temperature. Water was added and the resultingmixture was extracted twice with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified on a silica gelcolumn to afford 97 mg of intermediate MDI-215-2 with a yield of 77.1%.

¹H NMR (400 MHz, CDCl3) δ 9.33-9.32 (d, J=4.0 Hz, 1H), 8.52-8.48 (m,1H), 8.26-8.21 (m, 1H), 7.71-7.69 (m, 1H), 7.48 (dd, J=2.8 Hz, J=1.2 Hz,1H), 7.26 (dd, J=8.4 Hz, J=1.3 Hz, 1H), 7.18 (dd, J=8.4 Hz, J=2.4 Hz,1H), 7.04 (dd, J=11.6 Hz, J=4.2 Hz, 1H), 5.99 (d, J=22.2 Hz, 2H), 5.78(d, J=3.0 Hz, 2H), 5.40 (d, J=2.4 Hz, 1H), 5.34 (s, 2H), 5.25 (t, J=2.1Hz, 1H), 5.08-4.99 (m, 2H), 3.90-3.88 (m, 2H), 3.67-3.58 (m, 4H), 2.56(q, J=7.5 Hz, 2H), 1.10-0.77 (m, 9H), 0.06 (d, J=1.2 Hz, 9H), −0.01-0.10(m, 18H).

Synthesis of Compound MDI-215:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone

Intermediate MDI-215-2 (97 mg, 0.11 mmol) was dissolved in methanol (10ml), to which concentrated hydrochloric acid (5 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated togive a residue. The residue was dissolved in methanol and wasconcentrated to dryness, which was repeated 3 times. The resultingresidue was dissolve in methanol, 1 ml of aqueous ammonia was added, andthe mixture was concentrated, and purified by a preparation plate toafford 10 mg of the final product with a yield of 18.9%.

¹H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 12.83 (d, J=33.0 Hz, 1H),9.85 (s, 1H), 9.39 (dd, J=5.0 Hz, J=1.7 Hz, 1H), 8.37-8.31 (m, 1H), 8.07(s, 1H), 7.92 (dd, J=8.5 Hz, J=5.0 Hz, 1H), 7.40 (s, 1H), 7.13 (d, J=8.1Hz, 1H), 7.03 (d, J=11.9 Hz, 1H), 6.92 (d, J=9.1 Hz, 1H), 4.84-4.45 (m,4H), 2.49 (q, J=7.5 Hz, 2H), 1.02 (t, J=7.5 Hz, 3H).

Example 16:(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone(MDI-216)

Synthetic Route of MDI-216:

Synthesis Method:

Synthesis of Intermediate MDI-216-1:6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole

Tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(500 mg, 0.75 mmol),2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane(401 mg, 1.13 mmol), Pd(dppf)Cl2 (75 mg, 0.075 mmol) and potassiumphosphate (495 mg, 2.25 mmol) were dissolved in 1,4-dioxane (30 ml) andwater (6 ml).The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted for 16hours and cooled to room temperature. Water was added and the resultingmixture was extracted twice with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn. The purified product was dissolved in 25 ml of dichloromethane,and 5 ml of trifluoroacetic acid was added dropwise. The mixture wasstirred at room temperature for 30 minutes, and concentrated to give aresidue. The residue was dissolved in dichloromethane and wasconcentrated to dryness, which was repeated 3 times. The resultingresidue was purified with silica gel column to afford 210 mg ofintermediate MDI-216-1 with a yield of 39.2%.

¹H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8.3 Hz, 1H), 7.52 (d, J=7.4 Hz,1H), 7.49-7.37 (m, 5H), 7.25 (d, J=8.4 Hz, 1H), 7.23-6.96 (m, 2H), 5.93(s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.21 (d, J=35.1 Hz, 4H), 3.66-3.52(m, 4H), 2.54 (q, J=7.6 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m,4H), 0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

Synthesis of Intermediate MDI-216-2:(S)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-(benzyloxy)pyrrolidin-1-yl)ketone

Triphosgene (25.8 mg, 0.09 mmol) was dissolved in 5 ml oftetrahydrofuran, and intermediate MDI-216-1 (80 mg, 0.09 mmol) intetrahydrofuran (5 ml) was added dropwise at 0° C. The mixture wasstirred at room temperature for 10 minutes and (S)-3-(benzyloxy)pyrrolidine (31.9 mg, 0.18 mmol) in tetrahydrofuran was added. Themixture was stirred at room temperature for 5 minutes, and water wasadded. The resulting mixture was extracted twice with ethyl acetate, andthe organic phases were combined, washed with water and saturated brine,dried over aqueous sodium sulfate, concentrated, and purified by silicagel column to afford 71 mg of intermediate MDI-216-2 with a yield of86.1%.

¹H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H),7.47-7.42 (m, 3H), 7.39-7.29 (m, 6H), 7.24 (dd, J=8.4 Hz, J=4.0 Hz, 1H),7.07-6.97 (m, 2H), 5.95 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.92-4.88(m, 2H), 4.76-4.69 (m, 2H), 4.60 (s, 2H), 4.23 (s, 1H), 3.76-3.70 (m,2H), 3.66-3.58 (m, 6H), 2.54 (q, J=7.5 Hz, 2H), 2.15-2.13 (m, 1H),2.06-2.02 (m, 1H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.91 (m, 4H), −0.01-0.11(m, 18H).

Synthesis of Compound MDI-216:(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

Intermediate MDI-216-2 (83 mg, 0.11 mmol) was dissolved in methanol (10ml), to which 10 mg Pd/C and concentrated hydrochloric acid (5 ml) wereadded. The mixture was heated to 50° C., reacted for 6 hours, filteredand concentrated to give a residue. The residue was dissolved inmethanol and was concentrated to dryness, which was repeated 3 times.The resulting residue was dissolve in methanol, 1 ml of aqueous ammoniawas added, and then the mixture was concentrated, and purified by apreparation plate to afford 8 mg of the final product with a yield of15.2%.

¹H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.0 Hz,1H), 7.17 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.81-4.61 (m, 4H),4.46-4.44 (m, 1H), 3.79-3.69 (m, 2H), 3.50-3.43 (m, 2H), 2.56 (q, J=7.5Hz, 2H), 2.09-1.99 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

Example 17:5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol(MDI-217)

Synthetic Route of MDI-217:

Synthesis Method:

Synthesis of Intermediate MDI-217-1:5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo5[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)phenol

Tert-butyl 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (65.0 mg,0.08 mmol) was dissolved in 5 ml dichloromethane, and 1 mltrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes. Water was added, pH was adjusted withsaturated sodium bicarbonate to pH=9, and the resulting mixture wasextracted with DCM, washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated. The obtained solid wasdissolved in 1,2-dichloroethane, and 4-hydroxycyclohexanone (17.4 mg,0.15 mmol) was added, which was stirred at room temperature for 1 hour.And then sodium triacetyl borohydride (32.3 mg, 0.15 mmol) was added,and it was allowed to react at room temperature for 3 hours. Water wasadded to quench the reaction, and the resulting mixture was extractedwith DCM twice, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, concentrated,and purified by silica gel column to afford the product MDI-217-1 with ayield of 38.2%.

¹H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.44 (s,1H), 7.22 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.02-6.95 (m, 2H), 5.93 (d,J=4.0 Hz, 2H), 5.77 (d, J=4.0 Hz, 2H), 4.27-4.07 (m, 4H), 3.76-3.74 (m,1H), 3.65-3.56 (m, 4H), 2.76-2.74 (m, 1H), 2.55-2.49 (m, 2H), 2.11-2.03(m, 3H), 1.88-1.86 (m, 2H), 1.74-1.66 (m, 3H), 1.08 (t, J=4.0 Hz, 3H),0.94-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (s, 9H).

Synthesis of Compound MDI-217:5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

Intermediate MDI-217-1 (21.0 mg, 0.03 mmol) was dissolved in 4 ml ofmethanol, and 2 ml of concentrated hydrochloric acid was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated togive a residue. The residue was dissolved in methanol and wasconcentrated to dryness, which was repeated 3 times. To the resultingresidue, 1 ml of methanol was added, 2 ml of concentrated aqueousammonia was added for neutralization, and the mixture was concentratedto give a residue. The residue was dissolved in methanol and wasconcentrated to dryness, which was repeated 2 times. The resultingresidue was purified by a preparation plate to afford 5.3 mg of theproduct with a yield of 39.5%.

¹H NMR (400 MHz, MeOD-d4) δ 8.27 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.43-7.42(m, 1H), 7.19 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.96-6.88 (m, 2H), 3.98 (s,4H), 3.93 (m, 1H), 2.74-2.72 (m, 1H), 2.58 (q, J=8.0 Hz, 2H), 2.04-2.05(m, 1H), 1.90-1.80 (m, 5H), 1.64-1.62 (m, 2H), 1.10 (t, J=8.0 Hz, J=16.0Hz, 3H).

Example 18: 4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-218)

Synthetic Route of MDI-218:

Synthesis Method:

Synthesis of Intermediate MDI-218-1:6-bromo-3-(5-(cyclopropanesulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol

Tert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane, and 1 mltrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, concentrated, quenched with sodiumbicarbonate, and extracted twice with dichloromethane. The organicphases were combined, washed with water and saturated brine, dried overanhydrous sodium sulfate and concentrated. The obtained compound wasdissolved in 5 ml DCM and Et3N (0.08 ml, 0.59 mmol), and cooled to 0° C.Cyclopropylsulfonyl chloride (22.4 mg, 0.16 mmol) was slowly added. Itwas allowed to react at room temperature for 2 hours, and water wasadded to quench the reaction. The resulting mixture was extracted withDCM twice, and the organic phases were combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column to afford intermediate MDI-218-1 with ayield of 36.0%.

¹H NMR (400 MHz, CDCl3) δ 8.37 (d, J=8.0 Hz, 1H), 7.80 (d, J=4.0 Hz,1H), 7.43 (d, J=8.0 Hz, 1H), 5.91 (s, 2H), 5.73 (s, 2H), 4.75-4.74 (m,2H), 4.66-4.65 (m, 2H), 3.63-3.58 (m, 4H), 2.50-2.44 (m, 1H), 1.33-1.31(m, 2H), 1.06-1.02 (m, 2H), 0.96-0.91 (m, 4H), 0.00-0.05 (m, 18H).

Synthesis of Intermediate MDI-218-2:3-(5-cyclopropanesulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

The intermediate MDI-218-1 (36.0 mg, 0.05 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(25.5 mg, 0.06 mmol), Pd(dppf)Cl2 (3.9 mg, 0.005 mmol) and potassiumphosphate (34.2 mg, 0.16 mmol) were dissolved in 1,4-dioxane (6 ml) andwater (1 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heat to 100° C., reacted overnight,and cooled to room temperature. Water was added, and the resultingmixture was extracted twice with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford the intermediate MDI-218-2, the yield was 70.0%.

¹H NMR (400 MHz, CDCl3) δ 8.47 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.26 (d,J=7.9 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.04 (d, J=12.0 Hz, 1H), 5.95 (s,2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.76 (s, 2H), 4.68 (s, 2H), 3.88 (t,J=8.0 Hz, 2H), 3.68-3.57 (m, 4H), 2.56 (q, J=7.6 Hz, 2H), 2.24 (t, J=7.7Hz, 1H), 1.12-0.86 (m, 13H), −0.01-0.06 (m, 27H).

Synthesis of Compound MDI-218:4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

Intermediate MDI-218-2 (36.0 mg, 0.04 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml methanol, and pH was adjusted with sodiumbicarbonate to 8-9, and the resulting mixture was extracted 4 times withdichloromethane. The organic phases were combined, dried over anhydroussodium sulfate, and purified by a preparation plate to afford 16 mg ofthe final product with a yield of 81.4%.

¹H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.18(dd, J=8.0 Hz, J=4.0 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.65(s, 4H), 2.76-2.69 (m, 1H), 2.60-2.51 (m, 2H), 1.20-1.18 (m, 2H),1.10-1.06 (m, 5H).

Example 19:4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol(MDI-219)

Synthetic Route of MDI-219:

Synthesis Method

Synthesis of intermediate MDI-219-1:6-bromo-3-(5-(cyclobutylsulfonyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

Tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate(100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane, and 1 mltrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, concentrated, and quenched with sodiumbicarbonate. The resulting mixture was extracted twice withdichloromethane, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate andconcentrated. The obtained compound was dissolved in 5 ml DCM and Et3N(0.08 ml, 0.59 mmol), and cooled to 0° C. Cyclobutylsulfonyl chloride(24.6 mg, 0.16 mmol) was slowly added. It was allowed to react at roomtemperature for 2 hours, and water was added to quench the reaction. Theresulting mixture was extracted with DCM twice, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford intermediate MDI-219-1 with a yield of 32.1%.

¹H NMR (400 MHz, CDCl3) δ 8.36 (d, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.43 (d,J=8 Hz, 1H), 5.92 (d, J=4.0 Hz, 2H), 5.73 (s, 2H), 4.70 (s, 2H), 4.60(s, 2H), 4.03-3.95 (m, 1H), 3.65-3.56 (m, 4H), 2.75-2.64 (m, 2H),2.37-2.30 (m, 2H), 2.11-2.04 (m, 2H), 0.95-0.90 (m, 4H), 0.00-0.05 (m,18H).

Synthesis of Intermediate MDI-219-2:3-(5-(cyclobutylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

The intermediate MDI-219-1 (33.0 mg, 0.05 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(22.6 mg, 0.06 mmol), Pd(dppf)Cl₂ (3.5 mg, 0.005 mmol), and potassiumphosphate (30.2 mg, 0.14 mmol) were dissolved in 1,4-dioxane (6 ml) andwater (1 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added, the resulting mixturewas extracted twice with ethyl acetate, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-219-2 with a yield of 73.5%.

¹H NMR (400 MHz, CDCl3) δ 8.45 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.26(dd, J=8.3 Hz, J=1.3 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.07-7.02 (m, 1H),5.93 (s, 2H), 5.77 (s, 2H), 5.34 (s, 2H), 4.74-4.70 (m, 2H), 4.64-4.60(m, 2H), 4.00-3.98 (m, 1H), 3.91-3.86 (m, 2H), 3.66-3.58 (m, 4H),2.75-2.66 (m, 2H), 2.58-2.54 (m, 2H), 2.11-2.02 (m, 4H), 1.10-1.04 (m,3H), 1.01-0.96 (m, 6H), −0.02-0.05 (m, 27H).

Synthesis of Compound MDI-219:4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

Intermediate MDI-219-2 (31.0 mg, 0.04 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml methanol, and pH was adjusted with sodiumbicarbonate to pH=8-9. The resulting mixture was extracted withdichloromethane 4 times, and the organic phases were combined, driedover anhydrous sodium sulfate, and purified by a preparation plate toafford 12 mg of the final product with a yield of 65.7%.

¹H NMR (400 MHz, MeOD-d4) δ 8.26 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.17(dd, J=8.4 Hz, J=1.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.60(s, 4H), 4.26-4.18 (m, 1H), 2.68-2.52 (m, 4H), 2.40-2.31 (m, 2H),2.13-2.02 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

Example 20:4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol(MDI-220)

Synthetic Route of MDI-220:

Synthesis Method:

Synthesis of Intermediate MDI-220-1:6-bromo-3-(5-(cyclopentylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrol[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol

Tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate(100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane, and 1 mltrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, concentrated, and quenched with sodiumbicarbonate. The resulting mixture was extracted twice withdichloromethane, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate andconcentrated. The obtained compound was dissolved in 5 ml DCM and Et3N(0.08 ml, 0.59 mmol), and cooled to 0° C. Cyclopentylsulfonyl chloride(26.8 mg, 0.16 mmol) was slowly added and it was allowed to react atroom temperature for 2 hours. And then water was added to quench thereaction. The resulting mixture was extracted with DCM twice, and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford intermediate MDI-220-1 with a yield of38.1%.

¹H NMR (400 MHz, CDCl3) δ 8.36 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.43(dd, J=8.0 Hz, J=1.6 Hz, 1H), 5.90 (s, 2H)), 5.73 (s, 2H), 4.78-4.72 (m,2H), 4.68-4.62 (m, 2H), 4.33 (t, J=8.0 Hz, 1H), 3.63-3.57 (m, 4H),2.14-2.03 (m, 4H), 1.75-1.56 (m, 4H), 0.96-0.90 (m, 4H), −0.02-0.05 (m,18H).

Synthesis of Intermediate MDI-220-2:3-(5-(cyclopentylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

The intermediate MDI-220-1 (40 mg, 0.06 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(27.3 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol) and potassiumphosphate (36.5 mg, 0.17 mmol) were dissolved in 1,4-dioxane (6 ml) andwater (1 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added and the resultingmixture was extracted with ethyl acetate twice, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford intermediate MDI-220-2 with a yield of 62.9%.

¹H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.26(dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.04 (d, J=12.0Hz, 1H), 5.94 (s, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.80-4.75 (m, 2H),4.70-4.65 (m, 2H), 4.33 (t, J=8.0 Hz, 1H), 3.82-3.80 (m, 2H), 3.73-3.58(m, 4H), 2.58-2.53 (m, 2H), 2.18-2.05 (m, 4H), 1.79-1.58 (m, 4H),1.11-1.04 (m, 3H), 0.93-0.90 (m, 6H), −0.02-0.06 (m, 27H).

Synthesis of Compound MDI-220:4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

Intermediate MDI-220-2 (32.0 mg, 0.04 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml methanol, and pH was adjusted with sodiumbicarbonate to 8-9. The resulting mixture was extracted 4 times withdichloromethane, and the organic phases were combined, dried overanhydrous sodium sulfate, and purified by a preparation plate to afford10 mg of the final product with a yield of 55.8%.

¹H NMR (400 MHz, MeOD-d4) δ 8.27 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.43 (s,1H), 7.17 (dd, J=8.0 Hz, J=1.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz,2H), 4.65 (s, 4H), 3.91-3.83 (m, 1H), 2.58-2.52 (m, 2H), 2.13-2.03 (m,4H), 1.89-1.78 (m, 2H), 1.75-1.64 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

Example 21:5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol(MDI-221)

Synthetic Route of MDI-221:

Synthesis Method:

Synthesis of Intermediate 21: Tert-butyl2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

The intermediate tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(39.8 mg, 0.06 mmol), intermediate(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(27.1 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol) and potassiumphosphate (36.2 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 ml) andwater (2 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added and the resultingmixture was extracted twice with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford Intermediate 21 with a yield of 78%.

¹H NMR (400 MHz, CDCl3) δ8.46 (dd, J=12.0 Hz, J=8.0 Hz, 1H), 7.45 (s,1H), 7.24-7.21 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.01 (d, J=12.0 Hz, 1H),5.93 (d, J=12.0 Hz, 2H), 5.75 (s, 2H), 5.31 (s, 2H), 4.65-4.50 (m, 4H)),3.88-3.84 (m, 2H), 3.63-3.55 (m, 4H), 2.57-2.51 (m, 2H), 1.54 (s, 9H),1.07-1.03 (m, 3H), 0.90-0.85 (m, 4H), 0.03 (s, 9H), −0.07 (s, 18H).

Synthesis of Intermediate 22:5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-((2-trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

The intermediate Tert-butyl2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(40 mg, 0.046 mmol) was dissolved in 5 ml of dichloromethane, to which 1ml of trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and was concentrated todryness, which was repeated 3 times. The resulting residue was purifiedby silica gel column to afford Intermediate 22 with a yield of 43%.

¹H NMR (400 MHz, CDCl3) δ 8.44 (d, J=8.0 Hz, 1H), 7.20 (dd, J=8.3 Hz,J=1.4 Hz, 1H), 6.95 (dd, J=20.0 Hz, J=8.0 Hz, 1H), 5.91 (s, 2H), 5.47(s, 2H), 4.26-4.16 (m, 4H), 3.64-3.55 (m, 4H), 2.53-2.47 (m, 2H), 1.04(t, J=8.0 Hz, 3H), 0.92-0.86 (m, 4H), −0.07 (s, 9H), −0.08 (s, 9H).

Synthesis of Intermediate MDI-221-1:5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)phenol

5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-((2-trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol(40 mg, 0.064 mmol) and 1-methyl-1H-pyrazol-4-formaldehyde (8.5 mg,0.077 mmol) were dissolved in 5 ml 1,2-dichloroethane. It was allowed toreact at room temperature for 10 minutes. The reaction was cooled to 0°C. and sodium triacetoxyborohydride (26.9 mg, 0.128 mmol) was added.After the addition was completed, the mixture was warmed to roomtemperature and reacted for 1-2 h. After the completion of the reaction,water was added to quench the reaction, the resulting mixture wasextracted twice with dichloromethane, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford the intermediate MDI-221-1, yield 43.4%.

¹H NMR (400 MHz, CDCl3) δ 8.41 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.40 (d,J=4.0 Hz, 2H), 7.19-7.16 (m, 1H), 6.93 (dd, J=24.0 Hz, J=12.0 Hz, 2H),5.87 (s, 2H), 5.73 (s, 2H), 4.01-3.98 (m, 4H), 3.95 (s, 2H), 3.91 (s,3H), 3.62-3.52 (m, 4H), 2.51-2.45 (m, 2H), 1.01 (t, J=6.0 Hz, 3H),0.91-0.85 (m, 4H), −0.08 (s, 9H), −0.09 (s, 9H).

Synthesis of Compound MDI-221:5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

Intermediate MDI-221-1 (28 mg, 0.039 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml methanol, and 2 ml concentrated aqueousammonia was added and concentrated to give a residue. The residue wasdissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was purified by a preparationplate to afford 5.0 mg of the final product with a yield of 28%.

¹H NMR (400 MHz, MeOD-d4) δ 8.25 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.56(s, 1H), 7.42 (s, 1H), 7.16 (dd, J=8.4 Hz, J=1.4 Hz, 1H), 6.93 (dd,J=20.0 Hz, J=12.0 Hz, 2H), 4.03-3.96 (m, 6H), 3.92 (s, 3H), 2.58-2.53(m, 2H), 1.08 (t, J=8.0 Hz, 3H).

Example 22:4-(3-(5-cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol(MDI-224)

Synthetic Route of MDI-224:

Synthesis Method:

Synthesis of Intermediate MDI-224-1:4-(3-(5-(cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-((2-trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol(31.2 mg, 0.05 mmol) and cyclopentanone (5.1 mg, 0.06 mmol) weredissolved in 5 ml 1,2-dichloroethane. It was allowed to react at roomtemperature for 10 minutes. The reaction was cooled to 0° C., and sodiumtriacetoxyborohydride (21 mg, 0.1 mmol) was added. After the additionwas completed, the mixture was warmed to room temperature and reactedfor 1-2 h. After the completion of the reaction, water was added toquench the reaction, the resulting mixture was extracted twice withdichloromethane, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, concentrated,and purified by silica gel column to afford the intermediate MDI-221-1with a yield of 56.8%.

¹H NMR (400 MHz, CDCl3) δ 8.40 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.16(dd, J=8.3 Hz, J=1.4 Hz, 1H), 6.93 (dd, J=24.0 Hz, J=12.0 Hz, 2H), 5.89(s, 2H), 5.73 (s, 2H), 4.08 (s, 2H), 3.99 (s, 2H), 3.62-3.55 (m, 4H),3.22-3.19 (m, 1H), 2.50-2.45 (m, 2H), 1.98-1.89 (m, 2H), 1.84-1.75 (m,2H), 1.70-1.56 (m, 4H), 1.01 (t, J=8.0 Hz, 3H), 0.91-0.86 (m, 4H), −0.08(s, 9H), −0.09 (s, 9H).

Synthesis of Compound MDI-224:4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

Intermediate MDI-224-1 (25 mg, 0.036 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (5 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in methanol and 2 ml of concentrated aqueous ammoniawas added, and the mixture was concentrated to give a residue. Theresidue was dissolved in methanol, and was concentrated to dryness,which was repeated 3 times. The resulting residue was purified by apreparation plate to afford 7.0 mg of the final product with a yield of45.1%.

¹H NMR (400 MHz, MeOD-d4) δ 8.26 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.17(d, J=8.0 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.05-3.94 (m,4H), 3.27-3.25 (m, 1H), 2.59-2.54 (m, 2H), 2.08-2.01 (m, 2H), 1.87-1.79(m, 2H), 1.73-1.56 (m, 4H), 1.08 (t, J=8.0 Hz, 3H).

Example 23:5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol(MDI-225)

Synthetic Route of MDI-225:

Synthesis Method:

Synthesis of Intermediate MDI-225-1:5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)phenol

5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol(60 mg, 0.096 mmol) was dissolved in 5 ml 1,2-dichloroethane, andtetrahydropyrone (14 mg, 0.14 mmol) was added. The mixture was stirredat room temperature for 5 minutes, and sodium triacetyl borohydride (41mg, 0.19 mmol) was added. It was allowed to react at room temperaturefor 2 hours, and water was added to quench the reaction. The resultingmixture was extracted twice with DCM, and the organic phases werecombined, washed with water and saturated brine, dried with anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-225-1 with a yield of 51.4%.

¹H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.20(dd, J=8.0 Hz, J=1.4 Hz, 1H), 6.96 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 5.93(s, 2H), 5.76 (s, 2H), 4.08 (s, 4H), 4.00 (s, 2H), 3.66-3.56 (m, 4H),3.55-3.47 (m, 2H), 2.95-2.86 (m, 1H), 2.54-2.46 (m, 2H), 1.99-1.90 (m,2H), 1.80-1.71 (m, 2H), 1.04 (t, J=8.0 Hz, 3H), 0.95-0.87 (m, 4H),−0.03-0.08 (m, 18H).

Synthesis of Compound MDI-225:5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

Intermediate MDI-225-1 (35.0 mg, 0.05 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml methanol, and pH was adjusted with sodiumbicarbonate to 8-9. The resulting mixture was extracted 4 times withdichloromethane, and the organic phases were combined, dried overanhydrous sodium sulfate, and purified by a preparation plate to afford12 mg of the final product with a yield of 64.1%.

¹H NMR (400 MHz, MeOD-d4) δ 8.26 (dd, J=12.0 Hz, J=4.0 Hz, 1H), 7.42 (s,1H), 7.16 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz,2H), 4.07-3.99 (m, 6H), 3.52-3.49 (m, 2H), 2.95-2.90 (m, 1H), 2.58-2.53(m, 2H), 2.00-1.97 (m, 2H), 1.69-1.59 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

Example 24:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one(MDI-226)

Synthetic Route of MDI-226:

Synthesis Method:

Synthesis of Intermediate MDI-226-1:1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

Tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate(200 mg, 0.30 mmol) was dissolved in 10 ml dichloromethane, and 2 mltrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, concentrated, and quenched with sodiumbicarbonate. The resulting mixture was extracted twice withdichloromethane, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate andconcentrated. The obtained compound was dissolved in 10 ml DCM, and Et3N(0.16 ml, 1.18 mmol) was added. The mixture was cooled to 0° C., andacetyl chloride (25.0 mg, 0.32 mmol) was slowly added. It was allowed toreact at room temperature for 2 hours, and water was added to quench thereaction. The resulting mixture was extracted with DCM twice, and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford intermediate MDI-226-1 with a yield of54.8%.

¹H NMR (400 MHz, chloroform-d) δ 8.36-8.29 (m, 1H), 7.78-7.77 (m, 1H),7.42-7.39 (m, 1H), 5.93-5.88 (m, 2H), 5.71 (d, J=4 Hz, 2H), 4.76-4.73(m, 2H), 4.67-4.63 (m, 2H), 3.61-3.54 (m, 4H), 2.20 (s, 3H), 0.94-0.88(m, 4H)), −0.03-0.09 (m, 18H).

Synthesis of Intermediate MDI-226-2:1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

The intermediate MDI-226-1 (100 mg, 0.16 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(78.3 mg, 0.20 mmol), Pd(dppf)Cl2 (12.0 mg, 0.016 mmol) and potassiumphosphate (104.8 mg, 0.49 mmol) were dissolved in 1,4-dioxane (12 ml)and water (2 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added and the resultingmixture was extracted twice with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford the intermediate MDI-226-2 with a yield of 76.2%.

¹H NMR (400 MHz, chloroform-d) δ 8.52-8.45 (m, 1H), 7.49 (s, 1H),7.27-7.25 (m, 1H), 7.18 (d, J=8 Hz, 1H), 7.03 (d, J=12 Hz, 1H) 6.00-5.95(m, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.80-4.77 (m, 2H), 4.71-4.69 (m,2H), 3.90-3.86 (m, 2H), 3.66-3.58 (m, 4H), 2.59-2.54 (m, 2H), 2.22 (d,J=8 Hz, 3H), 1.10-1.06 (m, 3H), 1.03-0.91 (m, 6H), −0.02-0.06 (m, 27H).

Synthesis of Compound MDI-226:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

Intermediate MDI-226-2 (100 mg, 0.13 mmol) was dissolved in methanol (5ml), to which concentrated hydrochloric acid (2.5 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml of methanol, and pH was adjusted to 8-9 withaqueous ammonia. The resulting mixture was concentrated, and purified bysilica gel column to afford 5 mg of the final product with a yield of9.8%.

¹H NMR (400 MHz, methanol-d4) δ 8.28 (d, J=8 Hz, 1H), 7.43 (s, 1H), 7.18(d, J=8 Hz, 1H), 6.94 (dd, J=22, 10 Hz, 2H), 4.79 (s, 2H), 4.65 (s, 2H),2.59-2.53 (m, 2H), 2.23 (s, 3H), 1.08 (t, J=7.5 Hz, 3H).

Example 25:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one(MDI-227)

Synthetic Route of MDI-227:

Synthesis of Intermediate MDI-227-1:1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one

Tert-butyl2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate(200 mg, 0.30 mmol) was dissolved in 10 ml dichloromethane, and 2 mltrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, concentrated, and quenched with sodiumbicarbonate. The resulting mixture was extracted twice withdichloromethane, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate andconcentrated. The obtained compound was dissolved in 10 ml DCM and Et3N(0.16 ml, 1.18 mmol), and cooled to 0° C. Propionyl chloride (29 mg,0.32 mmol) was slowly added. It was allowed to react at room temperaturefor 2 hours, and water was added to quench the reaction. The resultingmixture was extracted with DCM twice, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-227-1 with a yield of 53.5%.

¹H NMR (400 MHz, chloroform-d) δ 8.39-8.32 (m, 1H), 7.77-7.76 (m, 1H),7.42-7.38 (m, 1H), 5.93-5.89 (m, 2H), 5.71 (d, J=4 Hz, 2H), 4.76-4.70(m, 2H), 4.65-4.63 (m, 2H), 3.61-3.55 (m, 4H), 2.46-2.40 (m, 2H),1.25-1.23 (m, 3H), 0.93-0.89 (m, 4H), −0.05-0.08 (m, 18H).

Synthesis of Intermediate MDI-227-2:1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one

The intermediate MDI-227-1 (100 mg, 0.16 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(76.5 mg, 0.19 mmol), Pd(dppf)Cl2 (11.8 mg, 0.016 mmol) and potassiumphosphate (102.4 mg, 0.48 mmol) were dissolved in 1,4-dioxane (12 ml)and water (2 ml).The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added, the resulting mixturewas extracted twice with ethyl acetate, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford the intermediate MDI-227-2 with a yield of 76.7%.

¹H NMR (400 MHz, chloroform-d) δ 8.52-8.45 (m, 1H), 7.48 (d, J=4 Hz,1H), 7.28-7.25 (m, 1H), 7.18 (d, J=8 Hz, 1H), 7.04 (d, J=12 Hz, 1H),5.98 (d, J=12 Hz, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.78 (s, 2H),4.69-4.68 (m, 2H), 3.90-3.86 (m, 2H), 3.66-3.58 (m, 4H), 2.59-2.54 (m,2H), 2.49-2.40 (m, 2H), 1.31-1.26 (m, 5H)), 1.10-1.05 (m, 3H), 0.96-0.91(m, 4H), −0.02-0.05 (m, 27H).

Synthesis of Compound MDI-227:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one

Intermediate MDI-227-2 (100 mg, 0.12 mmol) was dissolved in methanol (5ml), to which concentrated hydrochloric acid (2.5 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml of methanol and pH was adjusted to 8-9 withaqueous ammonia. The resulting mixture was concentrated, and purified bysilica gel column to afford 18 mg of final product with a yield of34.8%.

¹H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.80 (s, 1H), 9.85 (s, 1H),8.33 (d, J=8 Hz, 1H), 7.40 (s, 1H), 7.12 (d, J=8 Hz, 1H), 7.03 (d, J=12Hz, 1H), 6.92 (d, J=12 Hz, 1H), 4.73-4.58 (m, 2H), 4.50-4.42 (m, 2H),2.50-2.47 (m, 2H), 2.43-2.37 (m, 2H), 1.08-1.01 (m, 6H).

Example 26:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one(MDI-228)

Synthetic Route of MDI-228:

Synthesis Method:

Synthesis of Intermediate MDI-228-1:(1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one)

The intermediate tert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1ml of trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and was concentrated todryness, which was repeated 3 times. The resulting residue was dissolvedin 5 ml of DCM, and then triethylamine (24.3 mg, 0.24 mmol) was added.The temperature was lowered to 0° C., and isobutyryl chloride (19.2 mg,0.18 mmol) was slowly added dropwise. After the dropwise addition wascompleted, the mixture was warmed to room temperature and reacted for1-2 h. Water was added to the reaction to quench the reaction. Theliquids were separated, and the organic phase was dried over sodiumsulfate and concentrated by column chromatography to afford compoundMDI-228-1 with a yield of 58.7%.

¹H NMR (400 MHz, CDCl3) ¹H NMR (400 MHz, CDCl3) δ 8.39-8.32 (m, 1H),7.77-7.76 (m, 1H), 7.42-7.38 (m, 1H), 5.92-5.89 (m, 2H), 5.71-5.69 (m,2H), 4.83-4.64 (m, 4H), 3.63-3.55 (m, 4H), 2.81-2.70 (m, 1H), 1.22 (d,J=8 Hz, 6H), 0.98-0.86 (m, 4H), −0.05-0.08 (m, 18H).

Synthesis of Intermediate MDI-228-2:1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one

The intermediate MDI-228-1 (50.65 mg, 0.08 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(34.8 mg, 0. 1 mmol), Pd(dppf)Cl2 (5.9 mg, 0.008 mmol) and potassiumphosphate (50.9 mg, 0.24 mmol) were dissolved in 1,4-dioxane (10 ml) andwater (2 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added, and the resultingmixture was extracted twice with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated and purified by silica gel columnto afford intermediate MDI-228-2 with a yield of 77.5%.

¹H NMR (400 MHz, CDCl3) δ 8.49-8.42 (m, 1H), 7.46-7.45 (m, 1H),7.25-7.22 (m, 1H), 7.16 (d, J=8 Hz, 1H), 7.02 (d, J=12 Hz, 1H),5.97-5.92 (m, 2H), 5.76 (s, 2H), 5.32 (s, 2H), 4.83-4.67 (m, 4H),3.88-3.84 (m, 2H), 3.64-3.56 (m, 4H), 2.82-2.73 (m, 1H), 2.57-2.51 (m,2H), 1.22 (d, J=8 Hz, 6H), 1.08-0.99 (m, 5H), 0.93-0.88 (m, 4H), 0.03(s, 9H), −0.06-0.07 (m, 18H).

Synthesis of Compound MDI-228:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one

Intermediate MDI-228-2 (50 mg, 0.061 mmol) was dissolved in methanol (4ml), to which concentrated hydrochloric acid (2 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml methanol, 2 ml concentrated aqueous ammoniawas added, and the mixture was concentrated to give a residue. Theresidue was dissolved in methanol and was concentrated to dryness, whichwas repeated 3 times. The resulting residue was purified by apreparation plate to afford 15 mg of the final product with a yield of57.0%.

¹H NMR (400 MHz, MeOD-d4) δ 8.26 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.17(d, J=8 Hz, 1H), 6.93 (dd, J=20, 12 Hz, 2H), 4.83-4.59 (m, 4H),2.94-2.90 (m, 1H), 2.58-2.52 (m, 2H), 1.22 (d, J=8.0 Hz, 6H), 1.08 (t,J=8.0 Hz, 3H).

Example 27:2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one(MDI-229)

Synthetic Route of MDI-229:

Synthesis Method

Synthesis of Intermediate MDI-229-1:1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-cyclopropylethan-1-one

2-cyclopropylacetic acid (14.5 mg, 0.14 mmol) andN,N-diisopropylethylamine (46.6 mg, 0.36 mmol) were dissolved in DMF,and HATU (54.9 mg, 0.14 mmol) was added. It was allowed to react at roomtemperature for 10 minute. Intermediate tert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate(80.0 mg, 0.12 mmol) was dissolved in 5 ml dichloromethane, to which 1ml of trifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and was concentrated todryness, which was repeated 3 times. The resulting residue was dissolvedin DMF, and then was slowly added to the previous reaction solution. Itwas allowed to react at room temperature overnight, and water was addedto quench the reaction. The resulting mixture was extracted twice withethyl acetate, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, concentrated,and purified by silica gel column to afford intermediate MDI-229-1 witha yield of 57.8%.

¹H NMR (400 MHz, CDCl3) δ 8.40 (dd, J=8.0 Hz, J=20.0 Hz, 1H), 7.80 (s,1H), 7.44-7.41 (m, 1H), 5.92 (s, 2H), 5.74 (s, 2H), 4.78-4.66 (m, 4H),3.63-3.58 (m, 4H), 2.39-2.35 (m, 2H), 2.04 (s, 1H), 0.96-0.91 (m, 4H),0.66 (d, J=8.0 Hz, 2H), 0.27 (d, J=4.0 Hz, 2H), 0.02 (s, 18H).

Synthesis of Intermediate MDI-229-2:2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

The intermediate MDI-229-1 (45.0 mg, 0.07 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(33.1 mg, 0.08 mmol), Pd(dppf)Cl2 (5.1 mg, 0.007 mmol) and potassiumphosphate (44.3 mg, 0.21 mmol) were dissolved in 1,4-dioxane (20 ml) andwater (4 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added, the resulting mixturewas extracted twice with ethyl acetate, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford intermediate MDI-229-1 with a yield of 55.0%.

¹H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=8.0 Hz, J=16.0 Hz, 1H), 7.49 (s,1H), 7.27 (s, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H), 5.96(s, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.79-4.66 (m, 4H), 3.88 (t, J=8.0Hz, 2H), 3.66-3.58 (m, 4H), 2.59-2.54 (m, 2H), 2.39-2.36 (m, 2H),2.06-2.04 (m, 1H), 1.05 (t, J=8.0 Hz, 3H), 0.96-0.91 (m, 6H), 0.66-0.63(m, 2H), 0.28-0.26 (m, 2H), 0.06-0.05 (m, 27H).

Synthesis of Compound MDI-229:2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

The intermediate MDI-229-4 was dissolved in 4 ML methanol and 2 mlconcentrated hydrochloric acid was added. The mixture was heated to 50°C., reacted for 6 hours, and concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved 1 ml methanol and2 ml aqueous ammonia was added for neutralization, and the resultingmixture was concentrated to give a residue. The residue was dissolved inmethanol and was concentrated to dryness, which was repeated 2 times,thereby obtaining 3.8 mg of the product with a yield of 12.2%.

¹H NMR (400 MHz, MeOD-d4) δ 8.29 (d, J=8.0 Hz, 1H), 7.43 (s, 1H),7.19-7.17 (m, 1H), 6.98-6.90 (m, 2H), 4.73-4.61 (m, 4H), 2.59-2.53 (m,2H), 2.46 (d, J=8.0 Hz, 2H), 1.17 (m, 1H), 1.08 (t, J=8.0 Hz, 3H),0.64-0.59 (m, 2H), 0.30-0.26 (m, 2H).

Example 28:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one(MDI-230)

Synthetic Route of MDI-230:

Synthesis Method:

Synthesis of intermediate MDI-230-1:1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one

Tert-butyl2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(100 mg, 0.15 mmol) was dissolve in 5 ml of dichloromethane, and 1 ml oftrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 30 minutes, and concentrated to give a residue. Theresidue was dissolved in dichloromethane and was concentrated todryness, which was repeated 3 times. The resulting residue was dissolvedin 5 ml of dichloromethane and triethylamine (0.08 ml, 0.59 mmol) andcooled to 0° C. 3-methylbutyryl chloride (36.6 mg, 0.30 mmol) was slowlyadded. It was allowed to react at room temperature for 2 hours, andwater was added to quench the reaction. The resulting mixture wasextracted twice with dichloromethane, and the organic phases werecombined, washed with saturated brine, dried over anhydrous sodiumsulfate, concentrated, and purified by silica gel column to afford 64 mgof intermediate MDI-230-1, with a yield of 65.8%.

¹H NMR (400 MHz, CDCl3) δ 8.42-8.35 (m, 1H), 7.80-7.79 (m, 1H),7.45-7.41 (m, 1H), 5.96-5.91 (m, 2H), 5.74-5.73 (m, 2H), 4.78-4.69 (m,4H), 3.67-3.58 (m, 4H), 2.31-2.22 (m, 3H), 1.08-1.05 (m, 6H), 0.97-0.90(m, 4H), −0.02-0.05 (m, 18H).

Synthesis of Intermediate MDI-230-2:1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one

The intermediate MDI-230-1 (98 mg, 0.15 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(64 mg, 0.10 mmol), Pd(dppf)Cl2 (10 mg, 0.01 mmol) and potassiumphosphate (70 mg, 0.30 mmol) were dissolved in 1,4-dioxane (20 ml) andwater (4 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heat to 100° C., reacted for 16 h, andcooled to room temperature. Water was added, the resulting mixture wasextracted twice with ethyl acetate, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford 50 mg of intermediate MDI-230-2 with a yield of 59.7%.

¹H NMR (400 MHz, CDCl3) δ8.52-8.45 (m, 1H), 7.49 (s, 1H), 7.25 (d, J=2.8Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.04 (d, J=11.8 Hz, 1H), 5.98 (d,J=15.6 Hz, 2H), 5.78 (s, 2H), 5.36 (s, 2H), 4.78-4.72 (m, 4H), 3.91-3.86(m, 2H), 3.66-3.59 (m, 4H), 2.60-2.56 (m, 2H), 2.32-2.30 (m, 3H),1.11-1.01 (m, 6H), 0.99-0.89 (m, 7H), 0.03 (s, 9H), −0.03-0.05 (m, 18H).

Synthesis of Compound MDI-230:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one

The intermediate MDI-230-2 (50 mg, 0.06 mmol) was dissolved in methanol(6 ml), to which concentrated hydrochloric acid (3 ml) was added. It washeated to 50° C. and allowed to react for 6 hours. The reaction mixturewas concentrated to give a residue. The residue was dissolved inmethanol and concentrated to dryness (to remove hydrochloric acid),which was repeated 3 times. The resulting residue was dissolved inmethanol, to which 1 ml ammonia water was added. Then the mixture wasconcentrated and filtered, the filtrate was concentrated and purified bya preparation plate to afford 15 mg of the final product with a yield of55.9%.

¹H NMR (400 MHz, MeOD-d4) δ 8.29-8.26 (m, 1H), 7.43 (s, 1H), 7.19-7.16(m, 1H), 6.97-6.89 (m, 2H), 4.75-4.70 (m, 4H), 2.56 (q, J=7.5 Hz, 2H),2.36 (m, 2H), 2.29-2.20 (m, 1H), 1.10-1.05 (m, 9H).

Example 29:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)ketone(MDI-231)

Synthetic Route of MDI-231:

Synthesis Method:

Synthesis of Intermediate MDI-231-1:(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)ketone

Triphosgene (64.4 mg, 0.21 mmol) was dissolved in 15 ml ofdichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(150 mg, 0.21 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., followed by addition of triethylamine (63.6 mg, 0.63 mmol). Themixture was stirred at room temperature for 5 minutes and pyrrolidine(29.8 mg, 0.42 mmol) in dichloromethane was added. The resulting mixturewas stirred at room temperature for 10 minutes, and water was added. Theresulting mixture was extracted twice with ethyl acetate, and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford 140 mg of intermediate MDI-231-1 with ayield of 82.4%.

¹H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8 Hz, 1H), 7.53-7.38 (m, 6H), 7.22(d, J=8 Hz, 1H), 7.03 (d, J=12 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 5.96 (s,2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.81 (s, 2H), 4.67 (s, 2H), 3.66-3.59(m, 4H), 3.53-3.51 (m, 4H), 2.56-2.52 (m, 2H), 1.93-1.88 (m, 4H), 1.03(t, J=8 Hz, 3H), 0.93-0.87 (m, 4H), −0.05-0.09 (m, 18H).

Synthesis of Compound MDI-231:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)yl)(pyrrolidin-1-yl)ketone

Intermediate MDI-231-1 (140 mg, 0.173 mmol) was dissolved in methanol (6ml), to which 15 mg Pd/C was added and concentrated hydrochloric acid (3ml) was added dropwise. The mixture was heated to 50° C., reacted for 6hours, filtered, and concentrated to give a residue. The residue wasdissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in methanol, and 1ml of ammonia was added. The resulting mixture was concentrated, andpurified by a preparation plate to afford 21 mg of the final productwith a yield of 26.3%.

¹H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 12.69 (s, 1H), 9.83 (s, 1H),8.31 (d, J=8 Hz, 1H), 7.39 (s, 1H), 7.11 (d, J=8 Hz, 1H), 7.02 (d, J=12Hz, 1H), 6.91 (d, J=12 Hz, 1H), 4.57-4.56 (m, 2H), 4.49-4.48 (m, 2H),3.32-3.31 (m, 4H), 2.48-2.44 (m, 2H), 1.85-1.79 (m, 4H), 1.02 (t, J=7Hz, 3H).

Example 30:Azetidin-1-yl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone (MDI-232)

Synthetic Route of MDI-232:

Synthesis Method:

Synthesis of IntermediateMDI-232-1:Azetidin-1-yl(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone

Triphosgene (49.1 mg, 0.165 mmol) was dissolved in 15 ml oftetrahydrofuran, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(118 mg, 0.165 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0°C. and then triethylamine (50.0 mg, 0.495 mmol) was added. The mixturewas stirred at room temperature for 5 minutes, and azetidine (18.8 mg,0.330 mmol) in tetrahydrofuran was added. The resulting mixture wasstirred at room temperature for 10 minutes. Water was added and theresulting mixture was extracted twice with ethyl acetate, and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford 105 mg of intermediate MDI-232-1, with ayield of 79.8%.

¹H NMR (400 MHz, CDCl3) δ 8.52 (d, J=8.3 Hz, 1H), 7.58-7.55 (m, 2H),7.52-7.40 (m, 4H), 7.30-7.28 (m, 1H), 7.11-7.01 (m, 2H), 5.82 (s, 2H),5.43 (s, 2H), 5.27 (s, 2H), 4.78-4.61 (m, 4H), 4.22-4.19 (m, 4H),3.70-3.56 (m, 4H), 2.62 (q, J=7.5 Hz, 2H), 2.41-2.36 (m, 2H), 1.03 (t,J=7.5 Hz, 3H), 0.99-0.94 (m, 4H), 0.07 (d, J=2.7 Hz, 18H).

Synthesis of Compound MDI-232: Azetidin-1-yl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone

Intermediate MDI-232-1 (105 mg, 0.132 mmol) was dissolved in methanol (6ml), to which 11 mg Pd/C was added and concentrated hydrochloric acid (3ml) was added dropwise. The mixture was heated to 50° C., reacted for 6hours, filtered, and concentrated to give a residue. The residue wasdissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in methanol, and 1ml of ammonia was added. The resulting mixture was concentrated, andpurified by a preparation plate to afford 25 mg of the final productwith a yield of 42.6%.

¹H NMR (400 MHz, MeOD-d4) δ 8.29 (dd, J=8.4 Hz, J=4.0 Hz, 1H), 7.43 (s,1H), 7.19-7.16 (m, 1H), 6.97-6.90 (m, 2H), 4.62-4.53 (m, 4H), 3.69-3.66(m, 2H), 3.43-3.40 (m, 2H), 2.54 (q, J=7.5 Hz, 2H), 2.09-2.02 (m, 2H),1.06 (t, J=1.5 Hz, 3H).

Example 31:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone(MDI-233)

Synthetic Route of MDI-233:

Synthesis Method:

Synthesis of Intermediate MDI-233-1:(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone

Triphosgene (54.1 mg, 0.182 mmol) was dissolved in 5 ml oftetrahydrofuran, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(130 mg, 0.182 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0°C., followed by addition of triethylamine (55.2 mg, 0.550 mmol). Themixture was stirred at room temperature for 5 minutes, and piperidinehydrochloride (44.4 mg, 0.364 mmol) in tetrahydrofuran was added. Theresulting mixture was stirred at room temperature for 10 minutes. Waterwas added and the resulting mixture was extracted twice with ethylacetate, and the organic phases were combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column to afford 105 mg of intermediateMDI-233-1, with a yield of 66.6%.

¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=8.3 Hz, 1H), 7.50-7.48 (m, 2H),7.44-7.35 (m, 4H), 7.23-7.20 (m, 1H), 7.04-6.94 (m, 2H), 5.93 (s, 2H),5.74 (s, 2H), 5.20 (s, 2H), 4.69 (d, J=54.8 Hz, 4H), 3.64-3.56 (m, 4H),3.31 (s, 4H), 2.54 (q, J=7.5 Hz, 2H), 1.64 (s, 6H), 1.03 (t, J=7.5 Hz,3H), 0.93-0.86 (m, 4H), −0.07 (d, J=2.7 Hz, 18H).

Synthesis of Compound MDI-233:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone

Intermediate MDI-233-1 (100 mg, 0.121 mmol) was dissolved in methanol (6ml), to which 10 mg Pd/C was added and concentrated hydrochloric acid (3ml) was added dropwise. The mixture was heated to 50° C., reacted for 6hours, filtered, and concentrated to give a residue. The residue wasdissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in methanol, and 1ml of ammonia was added. The resulting mixture was concentrated, andpurified by a preparation plate to afford 33 mg of the final productwith a yield of 57.3%.

¹H NMR (400 MHz, MeOD-d4) δ 8.25 (d, J=8.4 Hz, 1H), 7.40 (s, 1H),7.16-7.14 (m, 1H), 6.95-6.87 (m, 2H), 4.83-4.65 (m, 4H), 3.35-3.33 (m,4H), 2.54 (q, J=7.5 Hz, 2H), 1.67-1.65 (m, 6H), 1.06 (t, J=7.5 Hz, 3H).

Example 32:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone(MDI-234)

Synthetic Route of MDI-234:

Synthesis Method:

Synthesis of Intermediate MDI-234-1:(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone

Triphosgene (54.1 mg, 0.182 mmol) was dissolved in 5 ml oftetrahydrofuran, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(130 mg, 0.182 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0°C., followed by addition of triethylamine (55.1 mg, 0.546 mmol). Themixture was stirred at room temperature for 5 minutes, and morpholine(31.7 mg, 0.364 mmol) in tetrahydrofuran was added. The resultingmixture was stirred at room temperature for 10 minutes. Water was addedand the resulting mixture was extracted twice with ethyl acetate, andthe organic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford 120 mg of intermediate MDI-234-1, with ayield of 79.7%.

¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H),7.47-7.35 (m, 4H), 7.26-7.23 (m, 1H), 7.06-6.97 (m, 2H), 5.96 (s, 2H),5.77 (s, 2H), 5.23 (s, 2H), 4.68 (d, J=54.8 Hz, 4H), 3.80-3.78 (m, 3H),3.67-3.59 (m, 4H), 3.43-3.40 (m, 3H), 3.27-3.21 (m, 6H), 2.54 (q, J=7.5Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.96-0.89 (m, 4H), −0.04 (d, J=2.7 Hz,18H).

Synthesis of Compound MDI-234:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone

Intermediate MDI-234-1 (120 mg, 0.145 mmol) was dissolved in methanol (6ml), to which 12 mg Pd/C was added and concentrated hydrochloric acid (3ml) was added dropwise. The mixture was heated to 50° C., reacted for 6hours, filtered, and concentrated to give a residue. The residue wasdissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in methanol, and 1ml of ammonia was added. The resulting mixture was concentrated, andpurified by a preparation plate to afford 42 mg of the final productwith a yield of 60.9%.

¹H NMR (400 MHz, MeOD-d4) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H),7.19-7.16 (m, 1H), 6.97-6.90 (m, 2H), 4.71-4.66 (m, 4H), 3.78-3.75 (m,4H), 3.41-3.39 (m, 4H), 2.54 (q, J=7.5 Hz, 2H), 1.06 (t, J=7.5 Hz, 3H).

Example 33:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)ketone(MDI-235)

Synthetic Route of MDI-235:

Synthesis Method:

Synthesis of Intermediate MDI-235-1:(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)ketone

Triphosgene (8.3 mg, 0.028 mmol) was dissolved in 5 ml oftetrahydrofuran, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(20 mg, 0.028 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0°C., followed by addition of triethylamine (8.5 mg, 0.084 mmol). Themixture was stirred at room temperature for 5 minutes, and1-methylpiperazine (5.60 mg, 0.056 mmol) in tetrahydrofuran was added.The resulting mixture was stirred at room temperature for 10 minutes.Water was added and the resulting mixture was extracted twice with ethylacetate, and the organic phases were combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column to afford 20 mg of intermediate MDI-235-1,with a yield of 85.1%.

¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=8.3 Hz, 1H), 7.50-7.48 (m, 2H),7.44-7.33 (m, 4H), 7.23-7.21 (m, 1H), 7.04-6.94 (m, 2H), 5.93 (s, 2H),5.75 (s, 2H), 5.20 (s, 2H), 4.70 (d, J=54.8 Hz, 4H), 3.64-3.56 (m, 4H),3.43-3.41 (m, 4H), 2.56-2.49 (m, 6H), 2.34 (s, 3H), 1.03 (t, J=7.5 Hz,3H), 0.93-0.86 (m, 4H), −0.07 (d, J=2.7 Hz, 18H).

Synthesis of Compound MDI-235:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)ketone

Intermediate MDI-235-1 (20 mg, 0.024 mmol) was dissolved in methanol (6ml), to which 5 mg Pd/C was added and concentrated hydrochloric acid (3ml) was added dropwise. The mixture was heated to 50° C., reacted for 6hours, filtered, and concentrated to give a residue. The residue wasdissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in methanol, and 1ml of ammonia was added. The resulting mixture was concentrated, andpurified by a preparation plate to afford 3 mg of the final product witha yield of 14.8%.

¹H NMR (400 MHz, MeOD-d4) δ 8.25 (d, J=8.4 Hz, 1H), 7.40 (s, 1H),7.16-7.14 (m, 1H), 6.95-6.87 (m, 2H), 4.83-4.66 (m, 4H), 3.44-3.41 (m,4H), 2.56-2.51 (m, 6H), 2.35 (s, 3H), 1.06 (t, J=7.5 Hz, 3H).

Example 34:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)ketone(MDI-236)

Synthetic Route of MDI-236:

Synthesis Method:

Synthesis of Intermediate MDI-236-1:(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)ketone

Triphosgene (54.07 mg, 0.182 mmol) was dissolved in 15 ml ofdichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(20 mg, 0.028 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., followed by addition of triethylamine (55.2 mg, 0.55 mmol). Themixture was stirred at room temperature for 5 minutes, and1-ethylpiperazine (41.5 mg, 0.364 mmol) in dichloromethane was added.The resulting mixture was stirred at room temperature for 10 minutes.Water was added and the resulting mixture was extracted twice with ethylacetate, and the organic phases were combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column to afford 100 mg of intermediateMDI-236-1, with a yield of 64.3%.

¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=8 Hz, 1H), 8.28 (s, 1H), 7.50-7.33(m, 5H), 7.22 (d, J=8 Hz, 1H), 7.03 (d, J=12 Hz, 1H), 6.95 (d, J=8 Hz,1H), 5.93 (s, 2H), 5.74 (s, 2H), 5.20 (s, 2H), 4.77 (s, 2H), 4.63 (s,2H), 3.63-3.61 (m, 4H), 3.43-3.42 (m, 4H), 2.53-2.46 (m, 8H), 1.03 (t,J=6 Hz, 3H), 0.93-0.86 (m, 7H), −0.06-−0.08 (m, 18H).

Synthesis of Compound MDI-236:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)ketone

Intermediate MDI-236-1 (100 mg, 0.117 mmol) was dissolved in methanol(10 ml), to which 10 mg Pd/C was added and concentrated hydrochloricacid (5 ml) was added dropwise. The mixture was heated to 50° C.,reacted for 6 hours, filtered, and concentrated to give a residue. Theresidue was dissolved in methanol and was concentrated to dryness, whichwas repeated 3 times. The resulting residue was dissolved in methanol,and 1 ml of ammonia was added. The resulting mixture was concentrated,and purified by a preparation plate to afford 21 mg of the final productwith a yield of 35.6%.

¹H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8 Hz, 1H), 7.43 (s, 1H), 7.17 (d,J=8 Hz, 1H), 6.96 (d, J=12 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 4.75-4.60 (m,4H), 3.48-3.44 (m, 4H), 2.61-2.48 (m, 8H), 1.17 (t, J=8 Hz, 3H), 1.08(t, J=8 Hz, 3H).

Example 35: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone(MDI-237)

Synthetic Route of MDI-237:

Synthesis Method:

Synthesis of Intermediate MDI-237-1:6-bromo-1H-pyrazolo[4,3-b]pyridine-3-formaldehyde

Sodium nitrite (2.81 g, 40.72 mmol) was dissolved in 12 ml DMF and 16 mlwater, and cooled to 0° C. Under nitrogen protection, 2N HCl (17.7 ml,35.4 mmol) was slowly added dropwise, and after the addition wascomplete, the reaction continued for 10 minutes. At 0° C.6-bromo-4-azaindole (1.0 g, 5.08 mmol) in DMF (8 ml) was slowly added tothe reaction solution dropwise. After the addition was completed, it wasallowed to react at room temperature overnight. After the reaction wascompleted, 50 ml of water was added to the reaction. The resultingmixture was stirred at room temperature for 0.5 hours, and filtered withsuction to afford 580 mg of intermediate MDI-237-1 with a yield of50.5%.

¹H NMR (400 MHz, DMSO) δ 14.52 (s, 1H), 10.27 (s, 1H), 8.80 (d, J=2.0Hz, 1H), 8.55 (d, J=2.0 Hz, 1H).

Synthesis of Intermediate MDI-237-2: 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-formaldehyde

The intermediate MDI-237-1 (250 mg, 1.11 mmol) was dissolved in 5 mlDMF, and then was cooled to 0° C. NaH (60%) (53.1 mg, 1.33 mmol) wasadded in batches at 0° C. After the addition was completed, it wasallowed to react for 30 minutes, and then SEMC1 (276.6 mg, 1.66 mmol)was added dropwise to the reaction. After the dropwise addition wascompleted, the temperature was raised to room temperature for reaction.After the reaction was completed, it was quenched with water, and theresulting mixture was extracted with ethyl acetate, and the organicphase was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated by column chromatography to afford 157.4 mg ofintermediate MDI-237-2 with a yield of 39.9%.

¹H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.39(d, J=2.0 Hz, 1H), 6.14 (s, 2H), 3.69-3.65 (m, 2H), 0.98-0.92 (m, 2H),−0.03 (s, 9H).

Synthesis of Intermediate MDI-237-3:6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-formaldehyde

The intermediate MDI-237-2 (176 mg, 0.49 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(196 mg, 0.49 mmol), Pd(dppf)Cl2 (36.1 mg, 0.05 mmol) and potassiumcarbonate (205 mg, 1.48 mmol) were dissolved in 1,4-dioxane (20 ml) andwater (4 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted overnight,and cooled to room temperature. Water was added, the resulting mixturewas extracted with ethyl acetate twice, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford 169.5 mg of intermediate MDI-237-3 with a yield of 62.7%.

¹H NMR (400 MHz, CDCl3) δ 10.58 (s, 1H), 8.76 (d, J=2.0 Hz, 1H), 8.08(d, J=2.0 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.02 (d, J=11.3 Hz, 1H), 6.19(s, 2H), 5.33 (s, 2H), 3.88-3.83 (m, 2H), 3.72-3.69 (m, 2H), 2.59-2.53(m, 2H), 1.10 (t, J=8.0 Hz, 3H), 1.02-0.94 (m, 4H), 0.03 (s, 9H), −0.03(s, 9H).

Synthesis of Intermediate MDI-237-4: tert-butyl2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

The intermediate MDI-237-3 (170 mg, 0.31 mmol) and tert-butyl3,4-diaminopyrroline-1-carboxylate (69.0 mg, 0.34 mmol) were dissolvedin 10 ml tert-butanol, to which I₂ (98.8 mg, 0.39 mmol) and K₂CO₃ (129mg, 0.93 mmol) were added. The mixture was heated to 70° C. and reactedfor 3 hours. After the reaction was completed, aqueous sodiumthiosulfate was added to quench the reaction. The resulting mixture wasextract twice with ethyl acetate, and the organic phases were combined,washed with water and saturated brine, dried with anhydrous sodiumsulfate, concentrated, and purified by silica gel column to afford 150mg of intermediate MDI-237-4 with a yield of 66.2%.

¹H NMR (400 MHz, CDCl3) δ 8.54 (d, J=1.9 Hz, 1H), 7.99 (d, J=1.9 Hz,1H), 7.20 (d, J=8.3 Hz, 1H), 7.01 (d, J=11.3 Hz, 1H), 6.60-6.20 (m, 2H),5.33 (s, 2H), 5.00-4.87 (m, 1H), 4.58-4.46 (m, 1H), 3.88-3.83 (m, 2H),3.79-3.64 (m, 6H), 2.58-2.52 (m, 2H), 1.57 (s, 9H), 1.09 (t, J=8.0 Hz,3H), 1.02-0.96 (m, 4H), 0.03 (s, 9H), −0.03 (s, 9H).

Synthesis of Intermediate MDI-237-5: Tert-butyl2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

Intermediate MDI-237-4 (100 mg, 0.14 mmol) and 2-iodoyl benzoic acid(77.0 mg, 0.28 mmol) were dissolved in 10 ml DMSO, heated to 45° C. andreacted for 5 hours. After the reaction was completed, the reaction wasquenched by aqueous sodium thiosulfate. The resulting mixture wasextracted twice with ethyl acetate, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford 75.0 mg of intermediate MDI-237-5, with a yield 75.2%.

¹H NMR (400 MHz, CDCl3) δ 11.78 (d, J=8.8 Hz, 1H), 8.52-8.50 (m, 1H),7.99-7.98 (m, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.03 (d, J=11.3 Hz, 1H), 6.44(s, 2H), 5.33 (s, 2H), 4.66-4.51 (m, 4H), 3.88-3.79 (m, 4H), 2.60-2.54(m, 2H), 1.54 (s, 9H), 1.11 (t, J=8.0 Hz, 3H), 1.03-0.98 (m, 4H), 0.03(s, 9H), −0.05 (s, 9H).

Synthesis of Intermediate MDI-237-6: tert-butyl2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

The intermediate MDI-237-5 (20.0 mg, 0.03 mmol) was dissolved in 10 mlof THF, the temperature was reduced to 0° C., and then NaH (60%) (1.2mg, 0.03 mmol) was added. The reaction mixture was stirred for 0.5hours. SEMC1 (5.1 mg, 0.03 mmol) was added to the mixture, which waswarmed to room temperature and stirred for 1 hour. After the reactionwas completed, water was added to quench the reaction. The resultingmixture was extracted twice with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated and purified by silica gel columnto afford 15.0 mg of intermediate MDI-237-6 with a yield of 63.5%.

¹H NMR (400 MHz, CDCl3) δ 8.54 (d, J=2.0 Hz, 1H), 8.00 (t, J=2.1 Hz,1H), 7.20 (d, J=8.3 Hz, 1H), 7.03 (d, J=11.4 Hz, 1H), 6.13 (d, J=4.5 Hz,2H), 5.57 (d, J=3.7 Hz, 2H), 5.33 (s, 2H), 4.66-4.50 (m, 4H), 3.88-3.84(m, 2H), 3.75-3.64 (m, 2H), 3.43-3.38 (m, 2H), 2.60-2.54 (m, 2H), 1.54(s, 9H), 1.11 (t, J=8.0 Hz, 3H), 1.02-0.98 (m, 2H), 0.93-0.88 (m, 2H),0.82-0.77 (m, 2H), 0.03 (s, 9H), −0.03 (s, 9H), −0.06 (s, 9H).

Synthesis of Intermediate MDI-237-7:cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

Intermediate MDI-237-6 (30.0 mg, 0.04 mmol) was dissolved in 10 ml DCM,to which zinc bromide (31.6 mg, 0.14 mmol) was added. The mixture wasstirred for 5 hours, and water was added to the reaction to quench thereaction. The resulting mixture was extracted twice with DCM, and theorganic phases were combined, washed with aqueous ammonia, then washedwith water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated. The crude product was dissolved in 10 ml DCM, to whichDIPEA (5.4 mg, 0.04 mmol) was added and then the mixture was cooled down0° C. Then, cyclopropylformyl chloride (4.4 mg, 0.04 mmol) was addeddropwise. After the addition was complete, the temperature was raised toroom temperature for reaction. After the reaction was completed, waterwas added to quench the reaction, and the resulting mixture wasextracted twice with DCM, and the organic phases were combined, washwith water and saturated brine, dried over anhydrous sodium sulfate, andconcentrate to afford 23.0 mg of crude MDI-237-7, which was directlyused in the next reaction. The crude yield was 79.6%.

Synthesis of Compound MDI-237: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

The intermediate MDI-237-7 (23.0 mg, 0.03 mmol) was dissolved in 4 mlMeOH, to which 2 ml concentrated hydrochloric acid was added. After theaddition, the temperature was raised to 50° C. for reaction. After 6hours of reaction, the temperature was lowered to room temperature, andthe reaction solvent was evaporated by concentration under reducedpressure. After that, 4 ml methanol and 0.5 ml aqueous ammonia wereadded. After concentration, the residue was subject to thin layerchromatography to afford 3.2 mg of white solid MDI-237 with a yield of26.5%.

¹H NMR (400 MHz, DMSO) δ 13.60 (s, 1H), 12.60-12.48 (m, 1H), 10.02 (s,1H), 8.53 (d, J=1.6 Hz, 1H), 7.95 (s, 1H), 7.16 (d, J=11.8 Hz, 1H), 6.98(d, J=9.1 Hz, 1H), 4.91-4.41 (m, 4H), 2.51-2.47 (m, 2H), 1.96-1.84 (m,1H)), 1.03 (t, J=8.0 Hz, 3H), 0.87-0.80 (m, 4H). LC-MS m/z (ESI) [M+H]+calculated value for C₂₃H₂₂FN₆O₂:433.2; measured value: 433.2.

Example 36: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone(MDI-239)

Synthetic Route of MDI-239:

Synthesis Method:

Synthesis of Intermediate MDI-239-1:6-bromo-4-methyl-1H-indazol-3-formaldehyde

Sodium nitrite (1.05 g, 15.2 mmol) was dissolved in 5 ml DMF and 5 mlwater, and cooled to 0° C. Under nitrogen protection, 3N HCl (4.5 ml,13.3 mmol) was slowly added dropwise, and the reaction was completeddropwise for 10 minutes. At 0° C. 6-bromo-4-methyl-1H-indole (400 mg,1.90 mmol) in DMF (20 ml) was slowly added to the reaction solutiondropwise. After the dropwise addition was completed, it was allowed toreact at room temperature overnight. The mixture was extracted withethyl acetate 3 times, and the organic phases were combined, washed 3times with water, washed with saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford 388 mg of intermediate MDI-239-1 with a yield of 84.3%.

¹H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 10.24 (s, 1H), 7.58 (d, J=1.3Hz, 1H), 7.27 (d, J=1.2 Hz, 1H), 2.90 (s, 3H).

Synthesis of Intermediate MDI-239-2:6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-formaldehyde

Intermediate MDI-239-1 (388 mg, 1.62 mmol) was dissolved in 25 ml of drytetrahydrofuran, and cooled to 0° C. Sodium hydride (60%) (117 mg, 4.86mmol) was slowly added, and the mixture was stirred for 10 minutes.2-(Trimethylsilyl)ethoxymethyl chloride (540 mg, 3.24 mmol) was addedslowly dropwise, and the reaction was carried out at room temperaturefor 1 hour. Water was added to quench the reaction, and the resultingmixture was extracted twice with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford 371 mg of intermediate MDI-239-2 with a yield of 61.9%.

¹H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.68 (s, 1H), 7.30 (s, 1H),5.78 (s, 2H), 3.61-3.57 (m, 2H), 2.89 (s, 3H), 0.96-0.89 (m, 2H), −0.02(s, 9H).

Synthesis of Intermediate MDI-239-3: tert-butyl2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

The intermediate MDI-239-2 (371 mg, 1.00 mmol) and tert-butyl3,4-diaminopyrroline-1-carboxylate (242 mg, 1.20 mmol) were dissolved in10 ml tert-butanol, followed by addition of iodine (317 mg, 1.25 mmol)and potassium carbonate (414 mg, 3.00 mmol), and the reaction wascarried out at 70° C. for 3 hours. The reaction was quenched by adding asaturated aqueous solution of sodium thiosulfate and the resultingmixture was extracted twice with ethyl acetate. The organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford 330 mg of intermediate MDI-239-3 with a yield of 60.0%.

¹H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.20 (s, 1H), 5.68 (s, 2H),4.77-4.66 (m, 2H), 3.77-3.60 (m, 4H), 3.57-3.53 (m, 2H), 2.89 (s, 3H),1.46 (s, 9H), 0.94-0.89 (m, 2H), −0.02 (s, 9H).

Synthesis of Intermediate MDI-239-4: tert-butyl2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

MDI-239-3 (330 mg, 0.60 mmol) was dissolved in 15 ml DMSO, and IBX (252mg, 0.90 mmol) was added. It was allowed to react at 50° C. for 16hours. The reaction was quenched by adding water, and resulting mixturewas extracted twice with ethyl acetate. The organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified on a silica gel column toafford 240 mg of intermediate MDI-239-4 with a yield of 73.0%.

¹H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.19 (s, 1H), 5.67 (s, 2H),4.62-4.50 (m, 4H), 3.67-3.54 (m, 2H), 2.98 (d, J=7.2 Hz, 3H), 1.55 (s,9H), 0.98-0.89 (m, 2H), −0.03 (s, 9H).

Synthesis of Intermediate MDI-239-5: tert-butyl2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

Intermediate MDI-239-4 (145 mg, 0.26 mmol) was dissolved in 15 ml of drytetrahydrofuran, and cooled to 0° C. Sodium hydride (60%) (19.0 mg, 0.79mmol) was slowly added, and the mixture was stirred for 10 minutes.2-(Trimethylsilyl)ethoxymethyl chloride (86.7 mg, 0.52 mmol) was addedslowly dropwise. After the addition, the reaction was carried out atroom temperature for 1 hour. The reaction was quenched by adding water,the resulting mixture was extracted twice with ethyl acetate, and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford 148 mg of intermediate MDI-239-5 with ayield of 84.0%.

¹H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.17 (s, 1H), 5.73 (s, 2H), 5.44(d, J=4.7 Hz, 2H), 4.65-4.51 (m, 4H), 3.61-3.57 (m, 2H), 3.38-3.34 (m,2H), 2.54 (d, J=5.8 Hz, 3H), 1.56 (s, 9H), 0.97-0.88 (m, 4H), −0.02 (s,9H), −0.11 (s, 9H).

Synthesis of Intermediate MDI-239-6:(2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(cyclopropyl)ketone

Intermediate MDI-239-5 (148 mg, 0.22 mmol) was dissolved in 15 ml ofdichloromethane, and zinc bromide (197 mg, 0.87 mmol) was added. Themixture was stirred at 25° C. for 4 hours, and 10 ml of aqueous ammoniawas added to the reaction solution. After liquid separation, the organicphase was washed with saturated sodium bicarbonate, and saturated sodiumchloride, dried over anhydrous sodium sulfate, and concentrated. Theconcentrate was dissolved in 10 ml of dichloromethane and triethylamine(66.8 mg, 0.66 mmol), and cooled to 0° C. Cyclopropionyl chloride (46.0mg, 0.44 mmol) was slowly added, and it was allowed to react at roomtemperature for 1 hour. The reaction was quenched by adding water. Theresulting mixture was extracted with dichloromethane twice, and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford intermediate MDI-239-6 94 mg, with a yieldof 65.8%.

¹H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.20 (s, 1H), 5.75 (s, 2H), 5.48(d, J=15.8 Hz, 2H), 5.00-4.69 (m, 4H), 3.63-3.59 (m, 2H), 3.46-3.34 (m,2H), 2.57 (d, J=7.7 Hz, 3H), 2.09-2.05 (m, 1H), 1.09-1.00 (m, 4H),0.98-0.89 (m, 4H), 0.00-0.05 (m, 18H).

Synthesis of Intermediate MDI-239-7:cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-4-methyl-1-((2-(trimethylsilanyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

The intermediate MDI-239-6 (40.0 mg, 0.06 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(36.8 mg, 0.09 mmol), tetrakistriphenylphosphine palladium (6.9 mg, 0.01mmol) and potassium phosphate (39.4 mg, 0.19 mmol) were dissolved in1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced withnitrogen, which was repeated 3 times. The mixture was heated to 100° C.,reacted for 16 hours, and cooled to room temperature. Water was added,the resulting mixture was extracted twice with ethyl acetate, and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified by asilica gel column to afford 27.3 mg of intermediate MDI-239-7 with ayield of 52.6%.

¹H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.17 (d, J=8.4 Hz, 1H),7.06-6.92 (m, 2H), 5.79 (d, J=7.0 Hz, 2H), 5.53 (d, J=14.4 Hz, 2H), 5.33(d, J=5.3 Hz, 2H), 5.00-4.69 (m, 4H), 3.90-3.86 (m, 2H), 3.64-3.58 (m,2H), 3.42-3.37 (m, 2H), 2.64-2.56 (m, 5H), 2.06-2.03 (m, 1H), 1.13-1.07(m, 4H), 1.05-1.01 (m, 3H), 0.95-0.89 (m, 6H), 0.02 (s, 9H), −0.03-0.12(m, 18H).

Synthesis of Compound MDI-239: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

Intermediate MDI-239-7 (27.3 mg, 0.03 mmol) was dissolved in methanol (6ml), to which concentrated hydrochloric acid (3 ml) was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated togive a residue. The residue was dissolved in methanol, and wasconcentrated to dryness, which was repeated 3 times. The resultingresidue was dissolved in methanol, and 1 ml aqueous ammonia was added.The mixture was concentrated, and filtered. The resulting filtrate wasconcentrated, and purified by a preparation plate to afford 5.1 mg ofthe final product with a yield of 34.7%.

¹H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 6.95-6.88 (m, 3H), 4.96 (s, 2H),4.66 (s, 2H), 2.63 (s, 3H), 2.55 (q, J=7.5 Hz, 2H), 1.98-1.92 (m, 1H),1.07 (t, J=7.5 Hz, 3H), 1.04-0.92 (m, 4H).

Example 37:(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone(MDI-240)

Synthetic Route of MDI-240

Synthesis Method:

Synthesis of Intermediate MDI-240-1: tert-butyl2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

Tert-butyl2-(6-bromo-4-methyl-1-(((2-(trimethylsilanyl)ethoxy)methyl)-1H-indazol-3-yl)-1-(((2-(trimethylsilanyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(60.0 mg, 0.09 mmol),2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane(47.2 mg, 0.13 mmol), tetrakistriphenylphosphine palladium (10.4 mg,0.01 mmol) and potassium phosphate (55.9 mg, 0.26 mmol) were dissolvedin 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replacedwith nitrogen, which was repeated 3 times. The mixture was heated to100° C., reacted for 16 hours, and cooled to room temperature. Water wasadded, the resulting mixture was extracted 2 times with ethyl acetate,and the organic phases were combined, washes with water and saturatedbrine, dried over anhydrous sodium sulfate, concentrated and purified bya silica gel column to afford 63.2 mg of the intermediate MDI-240-1 witha yield of 86.7%.

¹H NMR (400 MHz, CDCl3) δ 7.52 (d, J=7.4 Hz, 2H), 7.46-7.34 (m, 4H),7.03-6.96 (m, 3H), 5.77 (s, 2H), 5.50 (d, J=4.1 Hz, 2H), 5.22 (s, 2H),4.67-4.53 (m, 4H), 3.64-3.60 (m, 2H), 3.40-3.35 (m, 2H), 2.59-2.51 (m,5H), 1.56 (s, 9H), 1.06 (t, J=7.5 Hz, 3H), 0.98-0.89 (m, 4H), −0.04 (s,9H), −0.12 (s, 9H).

Synthesis of Intermediate MDI-240-2:(S)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

Intermediate MDI-240-1 (63.2 mg, 0.08 mmol) was dissolved in 10 ml ofdichloromethane, and zinc bromide (68.7 mg, 0.31 mmol) was added. Themixture was stirred at 25° C. for 4 hours, and 6 ml of aqueous ammoniawas added to the reaction solution. After liquid separation, the organicphase was washed with saturated sodium bicarbonate and saturated sodiumchloride, dried over anhydrous sodium sulfate, and concentrated. Theconcentrate was dissolved in 8 ml dichloromethane, at 0° C. triphosgene(22.5 mg, 0.08 mmol) was added, and triethylamine (76.7 mg, 0.76 mmol)was slowly added drop wise. The mixture was stirred at room temperaturefor 10 minutes, and (S)-pyrrolidine butan-3-ol (13.2 mg, 0.15 mmol) indichloromethane was added. The mixture was stirred at room temperaturefor 20 minutes. Water was added, the resulting mixture was extractedtwice with ethyl acetate, and the organic phases were combined, washedwith water and saturated brine, dried over anhydrous sodium sulfate,concentrated and purified by silica gel column to afford 44.0 mg ofintermediate MDI-240-2 with a yield of 68.9%.

¹H NMR (400 MHz, CDCl3) δ 7.51 (d, J=7.0 Hz, 2H), 7.45-7.34 (m, 4H),7.03-6.95 (m, 3H), 5.77 (s, 2H), 5.49 (s, 2H), 5.22 (s, 2H), 4.76-4.53(m, 4H), 4.46-4.44 (m, 1H), 3.64-3.54 (m, 4H), 3.44-3.33 (m, 4H),2.57-2.51 (m, 5H), 2.06-1.90 (m, 2H), 1.05 (t, J=7.5 Hz, 3H), 1.00-0.88(m, 4H), −0.04 (s, 9H), −0.13 (s, 9H).

Synthesis of Compound MDI-240:(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

MDI-240-2 (44.0 mg, 0.05 mmol) was dissolved in 6 ml methanol, to which5 mg 10% palladium on carbon was added. The atmosphere was replaced withhydrogen. It was allowed to react at 40° C. for 1 hour. After thereaction was completed, the resulting mixture was filtered, and thefiltrate was concentrated. The concentrate was dissolved in 6 mlmethanol, and 3 ml concentrated hydrochloric acid was added. It wasallowed to react for 7 hours at 50° C., and the mixture was concentratedto give a residue. The residue was dissolved in methanol and wasconcentrated to dryness, which was repeated 3 times. The resultingresidue was dissolved in 5 ml methanol, and 0.5 ml aqueous ammonia wasadded. The resulting mixture was concentrated, and purified by apreparation plate to afford 5.7 mg of the final product with a yield of22.3%.

¹H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 6.95-6.88 (m, 3H), 4.85-4.82 (m,2H), 4.62-4.59 (m, 2H), 4.46-4.45 (m, 1H), 3.79-3.69 (m, 2H), 3.64-3.57(m, 1H), 3.46-3.42 (m, 1H), 2.61 (s, 3H), 2.56 (q, J=7.5 Hz, 2H),2.09-1.98 (m, 2H), 1.07 (t, J=7.5 Hz, 3H).

Example 38:cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone(MDI-242)

Synthetic Route of MDI-242:

Synthesis Method:

Synthesis of Intermediate MDI-242-1:6-bromo-1H-pyrazolo[4,3-c]pyridine-3-formaldehyde

Sodium nitrite (1.68 g, 24.4 mmol) was dissolved in 15 ml DMF and 15 mlwater, and 3N HCl (7.1 ml, 21.3 mmol) was added at 0° C. The mixture wasstirred for 10 minutes, and 6-bromo-1H-pyrrolo[3,2-c]pyridine (600 mg,3.04 mmol) in DMF (15 ml) was added drop wise at 0° C. It was allowed toreact at room temperature for 30 minutes, and to react at 50° C. for 3hours. The resulting mixture was extracted 3 times with ethyl acetate,and the organic phases were combined, washed with water and saturatedbrine, dried over anhydrous sodium sulfate, concentrated, and purifiedby silica gel column to afford 350 mg of intermediate MDI-242-1 with ayield of 50.9%.

¹H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 9.25 (s, 1H), 7.88 (s, 1H).

Synthesis of Intermediate MDI-242-2: tert-butyl2-(6-bromo-1H-pyrazolo[4,3-c]pyridine-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

Intermediate MDI-242-1 (350 mg, 1.55 mmol) was dissolved in 15 mltert-butanol, followed by addition of tert-butyl3,4-diaminopyrrolidine-1-carboxylate (3734 mg, 1.86 mmol), potassiumcarbonate (775 mg, 5.57 mmol) and iodine (590 mg, 2.32 mmol). Themixture was stirred at 60° C. for 3 hours, and aqueous saturated sodiumthiosulfate was added. The resulting mixture was extracted 3 times withethyl acetate, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, concentrated,and purified by silica gel column to afford 240 mg of intermediateMDI-242-2 with a yield of 38.1%.

¹H NMR (400 MHz, CDCl3) δ 9.29 (d, J=0.9 Hz, 1H), 7.78 (d, J=1.0 Hz,1H), 5.00-4.95 (m, 1H), 4.52-4.49 (m, 1H), 3.77-3.70 (m, 3H), 3.57-3.53(m, 1H), 1.42 (s, 9H).

Synthesis of Intermediate MDI-242-3: Tert-butyl2-(6-bromo-1H-pyrazolo[4,3-c]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

Intermediate MDI-242-2 (240 mg, 0.59 mmol) was dissolved in 15 ml DMSO,and IBX (330 mg, 1.18 mmol) was added. The mixture was stirred overnightat 45° C., and extracted 3 times with ethyl acetate. The organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford 100 mg of intermediate MDI-242-3, with a yield of41.9%.

¹H NMR (400 MHz, CDCl3) δ 9.46 (d, J=6.1 Hz, 1H), 7.78 (s, 1H),4.65-4.53 (m, 4H), 1.54 (s, 9H).

Synthesis of Intermediate MDI-242-4: Tert-butyl2-(6-bromo-1H-pyrazolo[4,3-c]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

Intermediate MDI-242-3 (100 mg, 0.25 mmol) was dissolved in 15 ml THFand cooled to 0° C. NaH (60%) (21.7 mg, 0.54 mmol) was added and themixture was stirred at 0° C. for 20 minutes. After that, SEM-C1 (103 mg,0.62 mmol) was added. It was allowed to react for 2 hours. The resultingmixture was extracted 3 times with ethyl acetate, and the organic phaseswere combined, washed with water and saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified on silica gelcolumn to afford 100 mg of intermediate MDI-242-4 with a yield of 75.7%.

¹H NMR (400 MHz, CDCl3) δ 9.53-9.51 (m, 1H), 7.77 (d, J=1.2 Hz, 1H),5.85 (d, J=7.2 Hz, 2H), 4.65-4.52 (m, 4H), 3.66-3.61 (m, 2H), 1.54 (s,9H), 0.90-0.86 (m, 2H), −0.02 (s, 9H).

Synthesis of Intermediate MDI-242-5:(2-(6-bromo-1H-pyrazolo[4,3-c]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(cyclopropyl)ketone

Intermediate MDI-242-4 (100 mg, 0.19 mmol) was dissolved in 5 ml ofdichloromethane, and zinc bromide (168 mg, 0.75 mmol) was added. Themixture was stirred at room temperature for 4 hours and aqueous ammoniawas added. The resulting mixture was extracted twice withdichloromethane, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated. The obtained compound was dissolved in 5 ml ofdichloromethane, and triethylamine (56.6 mg, 0.56 mmol) was added. Themixture was cooled to 0° C., and cyclopropylformyl chloride (29.3 mg,0.28 mmol) was added. It was allowed to react at room temperature for 2hours. Water was added to quench the reaction, and the resulting mixturewas extracted twice with dichloromethane, and the organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified by silica gel column toafford 60.0 mg of intermediate MDI-242-5 with a yield of 63.8%.

¹H NMR (400 MHz, CDCl3) δ 9.53 (d, J=7.4 Hz, 1H), 7.78 (d, J=2.4 Hz,1H), 5.86 (s, 2H), 4.97-4.67 (m, 4H), 3.68-3.61 (m, 2H), 1.77-1.72 (m,1H), 1.13-1.09 (m, 2H), 0.99-0.89 (m, 4H), −0.05 (s, 9H).

Synthesis of Intermediate MDI-242-6: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

Intermediate MDI-242-5 (60 mg, 0.12 mmol) was dissolved in 5 ml dioxaneand 1 ml water, followed by addition of(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(56.7 mg, 0.14 mmol), Pd(PPh₃)₄ (13.8 mg, 0.01 mmol) and potassiumcarbonate (49.4 mg, 0.36 mmol). The atmosphere was replaced withnitrogen. The mixture was stirred at 100° C. for 2 hours. Water wasadded to quench the reaction, and the resulting mixture was extractedtwice with ethyl acetate, and the organic phases were combined, washedwith water and saturated brine, dried over anhydrous sodium sulfate,concentrated, and purified by silica gel column to afford 40 mg ofintermediate MDI-242-6 with a yield of 48.4%.

¹H NMR (400 MHz, CDCl3) δ 9.79 (d, J=8.7 Hz, 1H), 7.58 (d, J=1.2 Hz,1H), 7.26-7.18 (m, 2H), 5.95-5.90 (m, 2H), 5.33 (s, 2H), 5.00-4.70 (m,4H), 3.86-3.82 (m, 2H), 3.69-3.62 (m, 2H), 2.74-2.68 (m, 2H), 1.79-1.70(m, 1H), 1.14-1.08 (m, 5H), 1.02-0.96 (m, 4H), 0.92-0.88 (m, 2H), 0.03(s, 9H), −0.02-0.04 (m, 9H).

Synthesis of Compound MDI-242: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone(MDI-242)

Intermediate MDI-242-6 (40 mg, 0.06 mmol) was dissolved in 4 ml ofmethanol, and 2 ml of concentrated hydrochloric acid was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated. Thesolid was dissolved in 1 ml of methanol, and pH was adjusted withaqueous ammonia to 8-9. The resulting mixture was concentrated andpurified by a preparation plate to afford 8.0 mg of the final productwith a yield of 32.0%.

¹H NMR (400 MHz, MeOD) δ 9.61 (d, J=1.0 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H),7.16 (d, J=11.6 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 5.07-4.88 (m, 2H),4.68-4.62 (m, 2H), 2.69-2.64 (m, 2H), 1.98-1.89 (m, 1H), 1.09-1.05 (m,3H)), 1.01-0.98 (m, 2H), 0.96-0.94 (m, 2H).

Example 39:(R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone(MDI-243)

Synthetic Route of MDI-243:

Synthesis Method:

Synthesis of Intermediate MDI-243-1:(R)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

Triphosgene (54.1 mg, 0.18 mmol) was dissolved in 10 ml ofdichloromethane, and at 0° C., the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(130 mg, 0.18 mmol) in dichloromethane (5 ml), was added dropwise. Afterthe addition, anhydrous triethylamine (55.2 mg, 0.55 mmol) was addeddropwise. The mixture was stirred at room temperature for 10 minutes.TLC monitored that the raw materials disappeared. (R)-Pyrrolidin-3-ol(31.8 mg, 0.36 mmol) in dichloromethane (5 ml) was added. The resultingmixture was stirred at room temperature for 20 minutes. Water was addedto quench the reaction and the resulting mixture was extracted twicewith ethyl acetate, and the organic phases were combined, washed withsaturated brine, dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column to afford 118 mg of intermediateMDI-243-1, with a yield of 78.4%.

¹H NMR (400 MHz, CDCl3) δ 8.47 (d, J=8.3 Hz, 1H), 7.75-7.73 (m, 2H),7.47-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.96 (m, 2H), 5.96 (s,2H), 5.78 (s, 2H), 5.23 (s, 2H), 4.95-4.56 (m, 4H), 4.50-4.45 (m, 1H),3.79-3.72 (m, 2H), 3.66-3.58 (m, 5H), 3.46-3.42 (m, 1H), 2.54 (q, J=7.6Hz, 2H), 2.06-2.01 (m, 2H), 1.06 (t, J=7.5 Hz, 3H), 0.99-0.89 (m, 4H),0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

Synthesis of Compound MDI-243:(R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

MDI-243-1 (118 mg, 0.14 mmol) was dissolved in 20 ml methanol, and 20 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 12 ml methanol and 6 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 8 ml methanol,and 0.8 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 28 mg of the final product with ayield of 41.2%.

¹H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.0 Hz, 1H),7.17 (d, J=8.4 Hz, 1H), 6.98-6.90 (m, 2H), 4.82-4.60 (m, 4H), 4.47-4.45(m, 1H), 3.79-3.70 (m, 2H), 3.60-3.57 (m, 1H), 3.46-3.43 (m, 1H), 2.56(q, J=7.5 Hz, 2H), 2.09-1.98 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

Example 40:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylazetidin-1-yl)ketone(MDI-244)

Synthetic Route of MDI-244:

Synthesis Method:

Synthesis of Intermediate MDI-244-1:(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylazetidin-1-yl)ketone

Triphosgene (54.1 mg, 0.18 mmol) was dissolved in 10 ml ofdichloromethane, and at 0° C., the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(130 mg, 0.18 mmol) in dichloromethane (5 ml), was added dropwise. Afterthe addition, anhydrous triethylamine (185 mg, 1.8 mmol) was addeddropwise. The mixture was stirred at room temperature for 10 minutes.TLC monitored that the raw materials disappeared. Azetidine-3-ol (26.7mg, 0.36 mmol) in dichloromethane (5 ml) was added. The resultingmixture was stirred at room temperature for 20 minutes. Water was addedto quench the reaction and the resulting mixture was extracted twicewith ethyl acetate, and the organic phases were combined, washed withsaturated brine, dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column to afford 110 mg of intermediateMDI-244-1, with a yield of 74.3%.

¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=8.3 Hz, 1H), 7.73-7.51 (m, 2H),7.48-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.96 (m, 2H), 5.96 (s,2H), 5.76 (s, 2H), 5.23 (s, 2H), 4.73-4.58 (m, 4H), 4.39-4.31 (m, 2H),4.22-4.18 (m, 1H), 4.03-4.00 (m, 1H), 3.88-3.85 (m, 1H), 3.65-3.57 (m,4H), 2.54 (q, J=7.6 Hz, 2H), 1.05 (t, J=1.5 Hz, 3H), 0.99-0.89 (m, 4H),0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

Synthesis of Compound MDI-244:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylazetidin-1-yl)ketone

MDI-241-1 (110 mg, 0.14 mmol) was dissolved in 20 ml methanol, and 20 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 12 ml methanol and 6 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 8 ml methanol,and 0.8 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 34 mg of the final product with ayield of 54.4%.

¹H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18(d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.62-4.56 (m, 4H), 4.00-3.94 (m,1H), 3.70-3.66 (m, 1H), 3.62-3.55 (m, 1H), 3.51-3.46 (m, 1H), 3.41-3.37(m, 1H), 2.56 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H).

Example 41:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxylpiperidin-1-yl)ketone(MDI-245)

Synthetic Route of MDI-245:

Synthesis Method:

Synthesis of Intermediate MDI-245-1:(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-hydroxylpiperidin-1-yl)ketone

Triphosgene (54.1 mg, 0.18 mmol) was dissolved in 10 ml ofdichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(130 mg, 0.18 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., followed by addition of anhydrous triethylamine (185 mg, 1.8 mmol).The mixture was stirred at room temperature for 10 minutes. TLCmonitored that the raw materials disappeared. Piperidin-4-ol (36.9 mg,0.36 mmol) in dichloromethane (5 ml) was added. The resulting mixturewas stirred at room temperature for 20 minutes. Water was added toquench the reaction and the resulting mixture was extracted twice withethyl acetate, and the organic phases were combined, washed withsaturated brine, dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column to afford 116 mg of intermediateMDI-245-1, with a yield of 75.7%.

¹H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H),7.47-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.97 (m, 2H), 5.96 (s,2H), 5.75 (s, 2H), 5.37 (s, 2H), 4.79-4.66 (m, 4H), 3.95-3.92 (m, 1H),3.75-3.72 (m, 2H), 3.66-3.52 (m, 4H), 3.12-3.07 (m, 2H), 2.54 (q, J=7.6Hz, 2H), 2.02-1.91 (m, 2H), 1.68-1.63 (m, 2H), 1.06 (t, J=7.5 Hz, 3H),0.99-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

Synthesis of Compound MDI-245:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-hydroxylpiperidin-1-yl)ketone

MDI-243-1 (116 mg, 0.14 mmol) was dissolved in 20 ml methanol, and 20 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 12 ml methanol and 6 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 8 ml methanol,and 0.8 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 30 mg of the final product with ayield of 44.4%.

¹H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.72-4.65 (m, 4H), 3.88-3.82 (m, 1H),3.76-3.73 (m, 2H), 3.13-3.06 (m, 2H), 2.56 (q, J=7.5 Hz, 2H), 1.97-1.95(m, 2H), 1.63-1.55 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

Example 42:2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide(MDI-246)

MDI-246

Synthetic Route:

Synthesis Method:

Synthesis of Intermediate MDI-246-1:2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

Triphosgene (20.8 mg, 0.07 mmol) was dissolved in 5 ml of drydichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(50 mg, 0.07 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., then anhydrous triethylamine (70.9 mg, 0.70 mmol) was added slowly.The mixture was stirred at room temperature for 10 minutes. TLCmonitored that the raw materials disappeared. Methylamine hydrochloride(9.5 mg, 0.14 mmol) was added. The resulting mixture was stirred at roomtemperature for 2 hours. Water was added to quench the reaction and theresulting mixture was extracted twice with dichloromethane, and theorganic phases were combined, washed with saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford 42 mg of intermediate MDI-246-1, with a yield of 77.8%.

¹H NMR (400 MHz, CDCl3) δ 8.47 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H),7.47-7.37 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.07-6.96 (m, 2H), 5.96 (s,2H), 5.78 (s, 2H), 5.23 (s, 2H), 4.72-4.54 (m, 4H), 3.65-3.58 (m, 4H),2.64 (s, 3H), 2.56 (q, J=7.6 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H), 0.95-0.89(m, 4H), 0.02 (s, 9H), −0.04-−0.05 (m, 9H).

Synthesis of Compound MDI-246:2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

MDI-246-1 (42 mg, 0.055 mmol) was dissolved in 10 ml methanol, and 8 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 6 ml methanol and 3 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 5 ml methanol,and 0.5 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 10.3 mg of the final product with ayield of 45.1%.

¹H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.56 (s, 4H), 2.84 (s, 3H), 2.56 (q,J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H).

Example 43:2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide(MDI-247)

Synthetic Route of MDI-247:

Synthesis Method:

Synthesis of Intermediate MDI-247-1:2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

Triphosgene (22.9 mg, 0.08 mmol) was dissolved in 6 ml of drydichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(55 mg, 0.08 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., then anhydrous triethylamine (78.0 mg, 0.8 mmol) was added slowly.The mixture was stirred at room temperature for 10 minutes. TLCmonitored that the raw materials disappeared. Ethylamine hydrochloride(12.6 mg, 0.16 mmol) was added. The resulting mixture was stirred atroom temperature for 20 hours. Water was added to quench the reactionand the resulting mixture was extracted twice with ethyl acetate, andthe organic phases were combined, washed with saturated brine, driedover anhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford 47 mg of intermediate MDI-247-1, with a yield of 77.7%.

¹H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H),7.47-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.07-6.97 (m, 2H), 5.96 (s,2H), 5.78 (s, 2H), 5.23 (s, 2H), 4.72-4.54 (m, 4H), 3.65-3.58 (m, 4H),3.45-3.38 (m, 2H), 2.54 (q, J=7.6 Hz, 2H), 1.18-1.14 (m, 3H), 1.05 (t,J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

Synthesis of Compound MDI-247:2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

MDI-247-1 (47 mg, 0.06 mmol) was dissolved in 10 ml methanol, and 8 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 6 ml methanol and 3 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 5 ml methanol,and 0.5 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 11 mg of the final product with ayield of 42.4%.

¹H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 6.98-6.90 (m, 2H), 4.57 (s, 4H), 3.38-3.28 (m, 2H), 2.56(q, J=1.5 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).

Example 44:2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide(MDI-248)

Synthetic Route of MDI-248:

Synthesis Method:

Synthesis of Intermediate MDI-248-1:2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

Triphosgene (22.9 mg, 0.08 mmol) was dissolved in 6 ml ofdichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(55 mg, 0.08 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., then anhydrous triethylamine (78 mg, 0.8 mmol) was added slowly. Themixture was stirred at room temperature for 10 minutes. TLC monitoredthat the raw materials disappeared. Ethanolamine (9.4 mg, 0.16 mmol) indichloromethane (5 ml) was added. The resulting mixture was stirred atroom temperature for 1 hour. Water was added to quench the reaction andthe resulting mixture was extracted twice with dichloromethane, and theorganic phases were combined, washed with saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford 44 mg of intermediate MDI-248-1, with a yield of 71.3%.

¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=8.3 Hz, 1H), 7.73-7.51 (m, 2H),7.48-7.35 (m, 4H), 7.27-7.24 (m, 1H), 7.07-6.97 (m, 2H), 5.96 (s, 2H),5.78 (s, 2H), 5.23 (s, 2H), 4.73-4.57 (m, 4H), 3.65-3.53 (m, 6H),3.33-3.29 (m, 2H), 2.54 (q, J=7.6 Hz, 2H), 1.05 (t, J=1.5 Hz, 3H),0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (s, 9H).

Synthesis of Compound MDI-248:2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

MDI-248-1 (44 mg, 0.06 mmol) was dissolved in 10 ml methanol, and 8 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 6 ml methanol and 3 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 5 ml methanol,and 0.5 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 14 mg of the final product with ayield of 56.6%.

¹H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.59 (s, 4H), 3.68 (t, J=5.8 Hz, 2H),3.40 (t, J=5.8 Hz, 2H), 2.56 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H)

Example 45:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)Azetidin-3-nitrile(MDI-249)

Synthetic Route of MDI-249:

Synthesis Method:

Synthesis of Intermediate MDI-249-1:1-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-5-carbonyl)azetidine-3-nitrile

Triphosgene (15.8 mg, 0.05 mmol) was dissolved in 5 ml of drydichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(38 mg, 0.05 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., then anhydrous triethylamine (53.9 mg, 0.50 mmol) was added slowly.The mixture was stirred at room temperature for 10 minutes. TLCmonitored that the raw materials disappeared. Azetidine-3-nitrilehydrochloride (8.8 mg, 0.10 mmol) was added. The resulting mixture wasstirred at room temperature for 2 hours. Water was added to quench thereaction and the resulting mixture was extracted twice withdichloromethane, and the organic phases were combined, washed withsaturated brine, dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column to afford 26 mg of intermediate MDI-249-1,with a yield of 59.4%.

¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H),7.48-7.36 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.97 (m, 2H), 5.96 (s,2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.72-4.56 (m, 4H), 4.42-4.34 (m, 2H),4.26-4.17 (m, 2H), 3.65-3.58 (m, 4H), 3.46-3.39 (m, 1H), 2.53 (q, J=7.6Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H),−0.04-−0.05 (m, 9H).

Synthesis of Compound MDI-249:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5carbonyl)azetidin-3-nitrile

MDI-249-1 (26 mg, 0.03 mmol) was dissolved in 10 ml methanol, and 6 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 6 ml methanol and 3 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 5 ml methanol,and 0.5 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 5.3 mg of the final product with ayield of 33.5%.

¹H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.60 (s, 4H), 3.86-3.81 (m, 2H),3.65-3.53 (m, 2H), 3.19-3.13 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 1.08 (t,J=7.5 Hz, 3H).

Example 46:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidin-3-nitrile(MDI-250)

Synthetic Route of MDI-250:

Synthesis Method:

Synthesis of Intermediate MDI-250-1:1-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-5-carbonyl)pyrrolidine-3-nitrile

Triphosgene (14.9 mg, 0.05 mmol) was dissolved in 6 ml ofdichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(36 mg, 0.05 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., then anhydrous triethylamine (51.1 mg, 0.50 mmol) was added slowly.The mixture was stirred at room temperature for 10 minutes. TLCmonitored that the raw materials disappeared. Pyrrolidine-3-nitrilehydrochloride (9.7 mg, 0.10 mmol) was added. The resulting mixture wasstirred at room temperature for 20 minutes. Water was added to quenchthe reaction and the resulting mixture was extracted twice with ethylacetate, and the organic phases were combined, washed with saturatedbrine, dried over anhydrous sodium sulfate, concentrated, and purifiedby silica gel column to afford 26 mg of intermediate MDI-250-1, with ayield of 61.6%.

¹H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H),7.47-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.97 (m, 2H), 5.96 (s,2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.80-4.67 (m, 4H), 3.79-3.46 (m, 8H),3.12-3.05 (m, 1H), 2.54 (q, J=7.6 Hz, 2H), 2.38-2.16 (m, 2H), 1.05 (t,J=7.5 Hz, 3H), 0.96-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

Synthesis of Compound MDI-250:1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidin-3-nitrile

MDI-250-1 (26 mg, 0.03 mmol) was dissolved in 10 ml methanol, and 6 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 4 ml methanol and 3 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 5 ml methanol,and 0.5 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 6 mg of the final product with ayield of 39.8%.

¹H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d,7=8.4 Hz, 1H), 6.98-6.90 (m, 2H), 4.70 (s, 4H), 3.89-3.85 (m, 1H),3.78-3.76 (m, 1H), 3.70-3.59 (m, 2H), 3.23-3.18 (m, 1H), 2.56 (q, J=7.5Hz, 2H), 2.42-2.19 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

Example 47:2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide(MDI-251)

Synthetic Route of MDI-251:

Synthesis Method:

Synthesis of Intermediate MDI-251-1:2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide

Triphosgene (19.1 mg, 0.06 mmol) was dissolved in 6 ml of drydichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(46 mg, 0.06 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., then anhydrous triethylamine (65.3 mg, 0.6 mmol) was added slowly.The mixture was stirred at room temperature for 10 minutes. TLCmonitored that the raw materials disappeared. Tetrahydrofuran-3-aminehydrochloride (16.4 mg, 0.13 mmol) was added. It was allowed to react at38° C. for 5 hours. Water was added to quench the reaction and theresulting mixture was extracted twice with dichloromethane, and theorganic phases were combined, washed with saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford 32 mg of intermediate MDI-251-1, with a yield of 60.3%.

¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=8.3 Hz, 1H), 7.73-7.51 (m, 2H),7.47-7.35 (m, 4H), 7.27-7.24 (m, 1H), 7.07-6.97 (m, 2H), 5.96 (s, 2H),5.77 (s, 2H), 5.23 (s, 2H), 4.70-4.53 (m, 4H), 4.51-4.41 (m, 1H),4.06-3.58 (m, 8H), 2.54 (q, J=7.6 Hz, 2H), 2.40-1.99 (m, 2H), 1.05 (t,J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (s, 9H).

Synthesis of Compound MDI-251:2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

MDI-251-1 (32 mg, 0.04 mmol) was dissolved in 10 ml methanol, and 6 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 6 ml methanol and 3 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 5 ml methanol,and 0.5 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 3 mg of the final product with ayield of 16.3%.

¹H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.63 (s, 4H), 4.45-4.40 (m, 1H),4.03-3.94 (m, 2H), 3.87-3.81 (m, 1H), 3.71-3.68 (m, 1H), 2.56 (q, J=7.5Hz, 2H), 2.32-1.87 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

Example 48: Methyl2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(MDI-252)

Synthetic Route of MDI-252:

Synthesis Method:

Synthesis of Intermediate MDI-252-1: Methyl2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-((trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

Triphosgene (16.6 mg, 0.06 mmol) was dissolved in 5 ml of drydichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(40 mg, 0.06 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., then anhydrous triethylamine (56.8 mg, 0.56 mmol) was added slowly.The mixture was stirred at room temperature for 10 minutes. TLCmonitored that the raw materials disappeared. The reaction mixture wasconcentrated and was dissolved in 10 ml of methanol. DMAP (6.9 mg, 0.06mmol) was added. It was allowed to react at 70° C. for 4 hours. Thereaction mixture was concentrated to which water was added. Theresulting mixture was extracted twice with dichloromethane, and theorganic phases were combined, washed with saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford 30 mg of intermediate MDI-252-1, with a yield of 69.4%.

¹H NMR (400 MHz, CDCl3) δ 8.44-8.39 (m, 1H), 7.53-7.51 (m, 2H),7.48-7.36 (m, 4H), 7.23 (d, J=8.4 Hz, 1H), 7.05-6.96 (m, 2H), 5.95 (s,2H), 5.78 (s, 2H), 5.23 (s, 2H), 4.75-4.59 (m, 4H), 3.85 (s, 3H),3.66-3.57 (m, 4H), 2.53 (q, J=7.6 Hz, 2H), 1.04 (t, J=7.5 Hz, 3H),0.95-0.88 (m, 4H), 0.02 (s, 9H), −0.04-−0.05 (m, 9H).

Synthesis of Compound MDI-252: Methyl2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

MDI-252-1 (30 mg, 0.04 mmol) was dissolved in 10 ml methanol, and 6 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 6 ml methanol and 3 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 5 ml methanol,and 0.5 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 8 mg of the final product with ayield of 48.9%.

¹H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.61 (s, 4H), 3.83 (s, 3H), 2.56 (q,J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H).

Example 49: Ethyl2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate(MDI-253)

Synthetic Route of MDI-253:

Synthesis Method:

Synthesis of Intermediate MDI-253-1: Ethyl2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

Triphosgene (20.1 mg, 0.07 mmol) was dissolved in 5 ml of drydichloromethane, to which the intermediate6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole(48 mg, 0.07 mmol) in dichloromethane (5 ml) was added dropwise at 0°C., then anhydrous triethylamine (68.1 mg, 0.67 mmol) was added slowly.The mixture was stirred at room temperature for 10 minutes. TLCmonitored that the raw materials disappeared. The reaction mixture wasconcentrated and was dissolved in 10 ml ethanol. DMAP (8.2 mg, 0.07mmol) was added. It was allowed to react at 80° C. for 4 hours. Thereaction mixture was concentrated to which water was added. Theresulting mixture was extracted twice with dichloromethane, and theorganic phases were combined, washed with saturated brine, dried overanhydrous sodium sulfate, concentrated, and purified by silica gelcolumn to afford 33 mg of intermediate MDI-253-1, with a yield of 62.5%.

¹H NMR (400 MHz, CDCl3) δ 8.50-8.45 (m, 1H), 7.53-7.51 (m, 2H),7.47-7.37 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.07-6.96 (m, 2H), 5.96 (s,2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.72-4.59 (m, 4H), 4.29-4.25 (m, 2H),3.65-3.58 (m, 4H), 2.54 (q, J=7.6 Hz, 2H), 1.38-1.34 (m, 3H), 1.05 (t,J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (s, 9H).

Synthesis of Compound MDI-253: Ethyl2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

MDI-253-1 (33 mg, 0.04 mmol) was dissolved in 10 ml ethanol, and 6 mgpalladium on carbon was added. The atmosphere was replaced hydrogen. Itwas allowed to react at 40° C. for 1 hour. After the reaction wascompleted, the mixture was filtered, and the filtrate was concentrated.The concentrate was dissolved in 6 ml ethanol and 3 ml concentratedhydrochloric acid was added. It was allowed to react at 50° C. for 7hours and the mixture was concentrated to give a residue. The residuewas dissolved in ethanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in 5 ml ethanol,and 0.5 ml aqueous ammonia was added. The resulting mixture wasconcentrated, and purified to afford 10 mg of the final product with ayield of 54.8%.

¹H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.60 (s, 4H), 4.26 (q, J=7.1 Hz, 2H),2.57 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).

Example 50: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone(MDI-255)

Synthetic Route of MDI-255:

Synthesis Method:

Synthesis of Intermediate MDI-551-1:6-bromo-1H-pyrazolo[3,4-b]pyridine-3-formaldehyde

Sodium nitrite (2.80 g, 40.6 mmol) was dissolved in 15 ml DMF and 20 mlwater, and cooled to 0° C. 3N HCl (11.9 ml, 35.6 mmol) was slowly addeddropwise, and after the addition, the reaction was carried out for 10minutes. At 0° C. 6-bromo-1H-pyrrolo[2,3-b]pyridine (1.00 g, 5.08 mmol)in DMF (15 ml) was slowly added to the reaction solution dropwise. Afterthe addition, the mixture was heated to 50° C. It was allowed to reactfor 5 hours. The resulting mixture was extracted with ethyl acetate 3times, and the organic phases were combined, washed 3 times with water,washed with saturated brine, dried over anhydrous sodium sulfate,concentrated, and purified by silica gel column to afford 540 mg ofintermediate MDI-255-1 with a yield of 47.0%.

¹H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.70(d, J=8.0 Hz, 1H).

Synthesis of Intermediate MDI-255-2: Tert-butyl2-(6-bromo-1H-pyrazolo[3,4-b]pyridine-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

Intermediate MDI-255-1 (540 mg, 2.39 mmol) and tert-butyl3,4-diaminopyrroline-1-carboxylate (529 mg, 2.63 mmol) were dissolved in30 ml tert-butanol and stirred at room temperature for 30 minutes,followed by addition of I₂ (759 mg, 2.99 mmol) and K₂CO₃ (989.1 mg, 7.17mmol). The mixture was heated to 70° C. for 3 hours, and cooled to roomtemperature. Saturated sodium thiosulfate was added and the mixture wasstirred for 20 minutes until the color of iodine disappeared. Theresulting mixture was extracted twice with ethyl acetate, and theorganic phases were combined, washed with water and saturated brine,dried over anhydrous sodium sulfate, concentrated, and purified bysilica gel column to afford 396 mg of intermediate MDI-255-2 with ayield of 40.7%.

¹H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz,1H), 4.99-4.94 (m, 1H), 4.54-4.50 (m, 1H), 3.76-3.68 (m, 3H), 3.60-3.58(m, 1H), 1.45 (s, 9H).

Synthesis of Intermediate MDI-255-3: Tert-butyl2-(6-bromo-1H-pyrazolo[3,4-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

MDI-255-2 (396 mg, 0.97 mmol) was dissolved in 6 ml DMSO, and IBX (543mg, 1.94 mmol) was added. It was allowed to react at 50° C. for 6 hours.The reaction was quenched by adding water. The resulting mixture wasextracted twice with ethyl acetate and the organic phases were combined,washed with water and saturated brine, dried over anhydrous sodiumsulfate, concentrated, and purified on a silica gel column to afford 227mg of intermediate MDI-255-3 with a yield of 57.6%.

¹H NMR (400 MHz, CDCl3) δ 10.59 (s, 1H), 8.64 (dd, J=8.0 Hz, J=12.0 Hz,1H), 7.64 (d, J=8.0 Hz, 1H), 4.67-4.53 (m, 4H), 1.56 (s, 9H).

Synthesis of Intermediate MDI-255-4: Tert-butyl2-(6-bromo-1H-pyrazolo[3,4-b]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

Intermediate MDI-255-3 (227 mg, 0.56 mmol) was dissolved in 15 ml of drytetrahydrofuran, and cooled to 0° C., to which sodium hydride (60%)(67.2 mg, 1.68 mmol) was slowly added. The mixture was stirred for 10minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (280.3 mg, 1.68 mmol)was added slowly dropwise, and after the addition, the reaction wascarried out at room temperature for 1 hour. Water was added to quenchthe reaction. The resulting mixture was extracted twice with ethylacetate, and the organic phases were combined, washed with water andsaturated brine, dried over anhydrous sodium sulfate, concentrated, andpurified by silica gel column to afford 126 mg of intermediate MDI-255-4with a yield of 42.0%.

¹H NMR (400 MHz, CDCl3) δ 8.72 (dd, J=8.0 Hz, J=12.0 Hz, 1H), 7.63 (dd,J=8.0 Hz, J=4.0 Hz, 1H), 5.90 (d, J=8.0 Hz, 2H), 4.67-4.52 (m, 4H),3.69-3.64 (m, 2H), 1.56 (s, 9H), 1.01-0.97 (m, 2H), 0.02 (s, 9H).

Synthesis of Intermediate MDI-255-5: Tert-butyl2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

Intermediate MDI-255-4 (126 mg, 0.24 mmol),(2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane(143 mg, 0.36 mmol), Pd(PPh3)4 (27.2 mg, 0.02 mmol) and potassiumcarbonate (99.4 mg, 0.72 mmol) were dissolved in 1,4-dioxane (20 ml) andwater (4 ml). The atmosphere was replaced with nitrogen, which wasrepeated 3 times. The mixture was heated to 100° C., reacted for 3hours, cooled to room temperature. Water was added, and the resultingmixture was extracted twice with ethyl acetate. The organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, concentrated, and purified on a silica gel column toafford 83 mg of intermediate MDI-255-5 with a yield of 47.7%.

¹H NMR (400 MHz, CDCl3) δ 8.88 (dd, J=8.0 Hz, J=12.0 Hz, 1H), 7.52 (d,J=8.0 Hz, 1H), 7.25-7.21 (m, 2H), 5.95 (d, J=8.0 Hz, 2H), 5.36 (s, 2H),4.69-4.54 (m, 4H), 3.89-3.84 (m, 2H), 3.72-3.65 (m, 2H), 2.82-2.76 (m,2H)), 1.59 (s, 9H), 1.18-1.12 (m, 3H), 1.04-0.99 (m, 4H), 0.05 (s, 9H),0.02 (s, 9H).

Synthesis of Intermediate MDI-255-6:6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-3-(1-((2-(trimethylsilanyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine

Intermediate MDI-255-5 (83 mg, 0.11 mmol) was dissolved in 15 ml ofdichloromethane, and zinc bromide (103 mg, 0.46 mmol) was added. Themixture was stirred at 25° C. for 4 hours, and 10 ml of aqueous ammoniawas added to the reaction solution. After liquid separation, the organicphase was washed with saturated sodium bicarbonate and saturated sodiumchloride, dried over anhydrous sodium sulfate, and concentrated toafford 65 mg of intermediate MDI-255-6, with a yield of 95.6%. The crudeproduct was directly used in the next step.

Synthesis of intermediate MDI-255-7:(S)-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

Intermediate MDI-241-6 (20 mg, 0.03 mmol) was dissolved in 5 ml of drydichloromethane, and cooled to 0° C., to which triphosgene (9.5 mg, 0.03mmol) was added, and triethylamine (32.3 mg, 0.32 mmol) was addeddropwise. After the addition, the mixture was stirred at roomtemperature for 10 minutes, to which (S)-3-hydroxypyrrolidinehydrochloride (7.7 mg, 0.06 mmol) was added. The mixture was stirred atroom temperature for 1 hour. Water was added and the resulting mixturewas extracted twice with dichloromethane. The organic phases werecombined, washed with water and saturated brine, dried over anhydroussodium sulfate, and concentrated to afford 19 mg of intermediateMDI-255-7. The crude product was directly used in the next step.

Synthesis of Compound MDI-255:(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

Intermediate MDI-255-1 (19 mg, 0.03 mmol) was dissolved in 4 ml ofmethanol, to which 2 ml of concentrated hydrochloric acid was added. Themixture was heated to 50° C., reacted for 6 hours, and concentrated togive a residue. The residue was dissolved in methanol and wasconcentrated to dryness, which was repeated 3 times. The resultingresidue was dissolved in methanol to which 1 ml of aqueous ammonia wasadded to neutralize. The resulting mixture was concentrated and purifiedby a preparation plate to afford 4.9 mg of the final product 4.9 mg witha total yield of the two steps of 32.0%.

¹H NMR (400 MHz, DMSO) δ 13.61 (s, 1H), 10.22 (s, 1H), 8.78 (d, J=8.0Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.34 (d, J=12.0 Hz, 1H), 6.97 (d, J=8.0Hz, 1H), 4.93 (d, J=4.0 Hz, 1H), 4.75-4.42 (m, 4H), 4.30-4.27 (m, 1H),3.58-3.53 (m, 2H), 3.41-3.40 (m, 1H), 3.26-3.23 (m, 1H), 2.73-2.71 (m,2H), 2.01-1.79 (m, 2H), 1.09 (t, J=8.0 Hz, 3H).

Example 51:3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile(MDI-256)

Synthetic Route of MDI-256:

Synthesis Method:

Synthesis of intermediate MDI-256-1:3-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile

6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indole(50 mg, 0.07 mmol) was dissolved in 5 ml of dichloromethane, to whichEt3N (21.2 mg, 0.21 mmol) was added. The mixture was cooled to 0° C. andto which 2-cyanoacetyl chloride (8.7 mg, 0.08 mmol) was slowly added. Itwas allowed to react at room temperature for 1 hour, and water was addedto quench the reaction. The resulting mixture was extracted twice withdichloromethane, and the organic phases were combined, washed with waterand saturated brine, dried over anhydrous sodium sulfate, concentrated,and purified by silica gel column to afford 31 mg of intermediateMDI-256-1 with a yield of 56.7%.

Synthesis of Compound MDI-256:3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile

Intermediate MDI-256-1 (31 mg, 0.04 mmol) was dissolved in methanol (6ml), and 6 mg 10% Pd/C was added. The atmosphere was replaced withhydrogen 3 times. The mixture was heated to 40° C., reacted for 1 hour,filtered, and concentrated, to which 4 ml of methanol and 1 ml ofconcentrated hydrochloric acid were added. The mixture was heated to 50°C., reacted for 6 hours, and concentrated to give a residue. The residuewas dissolved in methanol and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in methanol, towhich 1 ml of aqueous ammonia was added to neutralize. The resultingmixture was concentrated and purified by a preparation plate to afford 3mg of the final product with a yield of 17.4%.

¹H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.18 (d,J=8.0 Hz, 1H), 6.97 (dd, J=8.0 Hz, J=20.0 Hz, 2H), 4.77-4.70 (m, 4H),3.62 (s, 2H), 2.59-2.53 (m, 2H), 1.09 (t, J=8.0 Hz, 3H).

Example 52:2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide(MDI-257)

Synthetic Route of MDI-257:

Synthesis Method:

Synthesis of Intermediate MDI-257-1:2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

The synthesis process was similar to that of the intermediate MDI-246-1with the exception that dimethylamine hydrochloride was used instead ofmethylamine hydrochloride.

Synthesis of Compound MDI-257:2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

Intermediate MDI-257-1 (41 mg, 0.05 mmol) was dissolved in methanol (6ml), and 8 mg 10% Pd/C was added. The atmosphere was replaced withhydrogen 3 times. The mixture was heated to 40° C., reacted for 1 hour,filtered, and concentrated, to which 4 ml of methanol and 1 ml ofconcentrated hydrochloric acid were added. The mixture was heated to 50°C., reacted for 6 hours, and concentrated to give a residue. The residuewas dissolved in methanol, and was concentrated to dryness, which wasrepeated 3 times. The resulting residue was dissolved in methanol, towhich 1 ml of ammonia was added to neutralize. The resulting mixture wasconcentrated and purified by a preparation plate to afford 8 mg of thefinal product with a yield of 35.2%.

¹H NMR (400 MHz, DMSO) δ 13.28 (s, 1H), 9.85 (s, 1H), 8.32 (d, J=8.0 Hz,1H), 7.40 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.03 (d, J=12.0 Hz, 1H), 6.93(d, J=12.0 Hz, 1H), 4.54-4.53 (m, 4H), 2.85 (s, 6H), 2.50-2.46 (m, 2H),1.04 (t, J=8.0 Hz, 3H).

Example 53:N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide(MDI-258)

Synthetic Route of MDI-258:

Synthesis Method:

Synthesis of Intermediate MDI-258-1:2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-(2-cyanoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

The synthesis process was similar to that of the intermediate MDI-246-1with the exception that 3-aminopropionitrile was used instead ofmethylamine hydrochloride.

Synthesis of Compound MDI-258:N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

Intermediate MDI-258-1 (36 mg, 0.04 mmol) was dissolved in methanol (4ml), and 3.6 mg 10% Pd/C was added. The atmosphere was replaced withhydrogen 3 times. The mixture was heated to 40° C., reacted for 1 hour,filtered, and concentrated. The concentrated product was dissolved in 4ml of methanol to which 2 ml of concentrated hydrochloric acid wasadded. The mixture was heated to 60° C., reacted for 6 hours, andconcentrated. The solid was dissolved in methanol, which was adjustedwith aqueous ammonia to pH=8-9. The resulting mixture was concentratedand purified by a preparation plate to afford 7.0 mg of the finalproduct with a yield of 34.2%.

¹H NMR (400 MHz, MeOD) δ 8.25 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.16 (d,J=8.4 Hz, 1H), 6.91 (dd, J=20.8, 10.3 Hz, 2H), 4.61-4.54 (m, 4H),3.55-3.50 (m, 2H), 2.66-2.51 (m, 4H), 1.06 (t, J=7.5 Hz, 3H).

Example 54:N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide(MDI-259)

Synthetic Route of MDI-259:

Synthesis Method:

Synthesis of Intermediate MDI-259-1:2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-cyclopropyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

The synthesis process was similar to that of the intermediate MDI-246-1with the exception that cyclopropylamine was used instead of methylaminehydrochloride.

Synthesis of Compound MDI-259:N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

Intermediate MDI-259-1 (36 mg, 0.04 mmol) was dissolved in methanol (4ml), and 3.6 mg 10% Pd/C was added. The atmosphere was replaced withhydrogen 3 times. The mixture was heated to 40° C., reacted for 1 hour,filtered, and concentrated. The concentrated product was dissolved in 4ml of methanol to which 2 ml of concentrated hydrochloric acid wasadded. The mixture was heated to 60° C., reacted for 6 hours, andconcentrated. The solid was dissolved in methanol, which was adjustedwith aqueous ammonia to pH=8-9. The resulting mixture was concentratedand purified by a preparation plate to afford 8.0 mg of the finalproduct with a yield of 39.6%.

¹H NMR (400 MHz, MeOD) δ 8.25 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.16 (dd,J=8.4, 1.4 Hz, 1H), 6.91 (dd, J=20.6, 10.4 Hz, 2H), 4.66-4.48 (m, 4H),2.68-2.62 (m, 1H), 2.59-2.53 (m, 2H), 1.08 (t, J=7.5 Hz, 3H), 0.76-0.71(m, 2H), 0.60-0.56 (m, 2H).

Example 55:N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide(MDI-260)

Synthetic Route of MDI-260:

Synthesis Method:

Synthesis of Intermediate MDI-260-1:2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-cyclobutyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

The synthesis process was similar to that of the intermediate MDI-246-1with the exception that cyclobutylamine was used instead of methylaminehydrochloride.

Synthesis of CompoundMDI-260:N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

Intermediate MDI-260-1 (37 mg, 0.04 mmol) was dissolved in methanol (4ml), and 3.7 mg 10% Pd/C was added. The atmosphere was replaced withhydrogen 3 times. The mixture was heated to 40° C., reacted for 1 hour,filtered, and concentrated. The concentrated product was dissolved in 4ml of methanol to which 2 ml of concentrated hydrochloric acid wasadded. The mixture was heated to 60° C., reacted for 6 hours, andconcentrated. The solid was dissolved in methanol, which was adjustedwith aqueous ammonia to pH=8-9. The resulting mixture was concentratedand purified by a preparation plate to afford 4.0 mg of the finalproduct with a yield of 19.0%.

¹H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 7.01-6.85 (m, 2H), 4.57 (s, 4H), 4.35-4.31 (m, 1H),2.59-2.53 (m, 2H), 2.36-2.30 (m, 2H), 2.11-2.04 (m, 2H), 1.76-1.69 (m,2H), 1.08 (t, J=7.5 Hz, 3H).

Example 56:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(2,6-diazaspiro[3.3]heptan-2-yl)ketone(MDI-261)

Synthetic Route of MDI-261:

Synthesis Method:

Synthesis of intermediate MDI-261-1: Tert-butyl6-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

The synthesis process was similar to that of the intermediate MDI-246-1with the exception that tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate was used instead ofmethylamine hydrochloride.

Synthesis of Compound MDI-261:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(2,6-diazaspiro[3.3]heptan-2-yl)ketone

Intermediate MDI-261-1 (52 mg, 0.06 mmol) was dissolved in methanol (6ml), and 10.1 mg 10% Pd/C was added. The atmosphere was replaced withhydrogen, which was repeated 3 times. The mixture was heated to 40° C.,reacted for 1 hour, filtered, and concentrated, followed by addition of4 ml of methanol and 1 ml of concentrated hydrochloric acid. The mixturewas heated to 50° C., reacted for 6 hours, and concentrated to give aresidue. The residue was dissolved in methanol, and was concentrated todryness, which was repeated 3 times. The resulting residue was dissolvedin methanol, to which 1 ml of ammonia was added to neutralize. Theresulting mixture was concentrated and purified by a preparation plateto afford 6 mg of the final product with a yield of 22.2%.

¹H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.19 (d,J=8.0 Hz, 1H), 6.95 (dd, J=12.0 Hz, J=12.0 Hz, 2H), 4.90 (s, 2H), 4.66(s, 2H), 4.22 (d, J=12.0 Hz, 2H), 4.02-3.94 (m, 4H), 3.60 (d, J=4.0 Hz,2H), 2.59-2.54 (m, 2H), 1.09 (t, J=8.0 Hz, 3H).

Example 57:(S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol(MDI-262)

Synthetic Route of MDI-262:

Synthesis Method:

Synthesis of Intermediate MDI-262-1: Tert-butyl(S)-2-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidin-1-carboxylate

Tert-butyl 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (65.0 mg,0.08 mmol) was dissolved in 10 ml DCM, to which zinc bromide (68.6 mg,0.31 mmol) was added. The mixture was stirred for 5 hours, and water wasadded to quench the reaction. The resulting mixture was extracted withDCM twice, and the organic phases were combined, washed with aqueousammonia, then washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated. The obtained crude productwas dissolved in 10 ml DMF, to which Boc-L-proline (19.7 mg, 0.09 mmol),HATU (34.71 mg, 0.09 mmol), and DIPEA (11.8 mg, 0.09 mmol) were added.After the addition, it was allowed to react at room temperature. Waterwas added to quench the reaction. The resulting mixture was extractedtwice with ethyl acetate, and the organic phases were combined, washedwith water and saturated brine, dried over anhydrous sodium sulfate andconcentrated to afford 43.0 mg of intermediate MDI-262-1 with a yield of59.4%.

¹H NMR (400 MHz, CDCl3) δ 8.50-8.41 (m, 1H), 7.47-7.45 (m, 1H),7.25-7.22 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.01 (d, J=10.3 Hz, 1H),6.05-5.87 (m, 2H), 5.76-5.75 (m, 2H), 5.31 (s, 2H), 5.02-4.23 (m, 5H),3.89-3.83 (m, 2H), 3.70-3.42 (m, 6H), 2.57-2.51 (m, 2H), 2.37-1.88 (m,3H), 1.73-1.70 (m, 1H), 1.47 (s, 9H), 1.07-0.98 (m, 5H), 0.94-0.88 (m,4H), 0.03 (s, 9H), −0.06-0.08 (m, 18H).

Synthesis of Compound MDI-262:(S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole

The intermediate MDI-262-1 (33.0 mg, 0.04 mmol) was dissolved in 4 mlMeOH, to which 2 ml concentrated hydrochloric acid was added. After theaddition, the temperature was raised to 50° C. for reaction. After 6hours of reaction, the temperature was reduced to room temperature, andthe reaction solvent was evaporated by concentration under reducedpressure, followed by addition of 4 ml methanol and 0.5 ml aqueousammonia. After concentration, the residue was subject to thin layerchromatography to afford 1.8 mg of white solid MDI-262 with a yield of11.3%.

¹H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.18 (d,J=8.5 Hz, 1H), 6.96 (d, J=11.7 Hz, 1H), 6.91 (d, J=8.9 Hz, 1H),4.80-4.64 (m, 4H), 4.09-4.05 (m, 1H), 3.26-3.22 (m, 2H), 2.59-2.53 (m,2H), 2.06-1.86 (m, 4H), 1.08 (t, J=8.0 Hz, 3H). LC-MS m/z (ESI) [M+H]⁺calculated value for C₂₅H₂₆FN₆O₂: 461.2; measured value: 461.2.

Example 58:(R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol(MDI-263)

The synthesis process was similar to that of MDI-262, with the exceptionthat Boc-D-proline was used instead of Boc-L-proline.

¹H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 6.96 (d, J=12.2 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H),4.82-4.60 (m, 4H), 4.21-4.15 (m, 1H), 3.33-3.23 (m, 1H), 3.08-2.99 (m,1H), 2.59-2.53 (m, 2H), 2.08-1.86 (m, 4H), 1.08 (t, J=8.0 Hz, 3H).

Example 59: Evaluation I of Pharmacological Activity

1. Experimental Principle

A drug screening system based on kinases JAK1, JAK2, JAK3, and TYK2 wasused to detect the inhibitory ability of small molecule compounds onkinase activity. A kinase undergoes an enzymatic reaction with itssubstrates IRS1, IGF1Rtide, and Poly (4:1 Glu, Tyr), consuming ATP toproduce ADP, wherein the ADP-Glo reagent and luminescence method can beused to detect the amount of the product to reflect the activity of thekinase.

2. Experimental Scheme

2.1 Experimental Materials and Instruments

Item Name Source/Supplier Catalogue No. 1 HEPES Life Technologies15630-080 2 BRIJ 35 detergent (10%) Merck 203728 3 MgCl2 Sigma M1028 4EGTA Sigma E3889 5 ADP-Glo Kinase Assay Promega V9101 6 JAK1 InvitrogenPV4774 7 JAK2 Invitrogen PV4210 8 JAK3 Invitrogen PV3855 9 TYK2Invitrogen PV4790 10 ATP Promega V915B 11 IRS1 Signalchem I40-58-1000 12IGF1Rtide Signalchem I15-58 13 Poly (4:1 Glu, Tyr) Sigma P0275 14Topseal A PerkinElmer E5341 15 OptiPlate-384 PerkinElmer 6007290 16384-Well Polypropylene Labcyte PP-0200 microplate 17 Envision PerkinElmer 2104 18 Echo Labcyte 550 19 Centrifuge Eppendorf 5810R

2.2 Experimental Methods

2.2.1 Kinase Reaction Reagent Formulation

2.2.1.1 1× Kinase Reaction Buffer (400 mL)

Stock Name Concentration Volume Final Concentration HEPES 1 M (20×)  20mL 50 mM MgCl₂ 1 M (100×) 4 mL 10 mM BRIJ-35 10% (1000×) 400 μL 0.01%EGTA Powder 152 mg  1 mM ddH2O 375.6 mL2 mM DTT, ready to use

2.2.1.2 2× Kinase Formulation

JAK1 kinase solution 2× Final Final Name Stock concentration VolumeConcentration Concentration JAK1 7072.4 nM (884×) 0.8 μL 8 nM 4 nM 1×Kinase Reaction Buffer 706.5 μL

JAK2 kinase solution 2× Final Final Name Stock concentration VolumeConcentration Concentration JAK2 4955 nM (4955×) 0.2 μL 1 nM 0.5 nM 1×Kinase Reaction Buffer 990.8 μL

JAK3 kinase solution 2× Final Final Name Stock concentration VolumeConcentration Concentration JAK3 5341.2 nM (5341.2×) 0.2 μL 1 nM 0.5 nM1× Kinase Reaction Buffer 1068 μL

TYK2 kinase solution 2× Final Final Name Stock concentration VolumeConcentration Concentration TYK2 6104.7 nM (763×) 1 μL 8 nM 4 nM 1×Kinase Reaction Buffer 762 μL

2.2.1.3 2× Substrate Mixture Formulation

JAK1 substrate mixture solution 2× Final Final Name Stock concentrationVolume Concentration Concentration ATP 10 mM (250×) 2.8 μL 40 μM 20 μMIRS1 1 mg/mL (10×) 70 μL 0.1 mg/mL 0.05 mg/mL 1× Kinase Reaction 627.2μL Buffer

JAK2 substrate mixture solution Stock 2× Final Final Name ConcentrationVolume concentration Concentration ATP 10 mM (500×) 1.4 μL 20 μM 10 μMIGF1Rtide 1 mg/mL (50×) 14 μL 0.02 mg/mL 0.01 mg/mL 1× Kinase ReactionBuffer 684.6 μL

JAK3 substrate mixture solution Stock 2× Final Final Name concentrationVolume Concentration Concentration ATP 10 mM (500×) 1.4 μL 20 μM 10 μMPoly (4:1 Glu, Tyr) Peptide 5 mg/mL (83.3×) 8.4 μL 0.06 mg/mL 0.03 mg/mL1× Kinase Reaction Buffer 690.2 μL

TYK2 substrate mixture solution Stock 2X Final Final Name ConcentrationVolume concentration Concentration ATP 10 mM 1.4 μL 20 μM 10 μM (500X)IRS1 1 mg/mL 42 μL 0.06 mg/mL 0.03 mg/mL (16.67X) 1X Kinase 656.6 μLReaction Buffer

2.2.1.4 Compounds to be Tested

Name Mass/mg Molecular weight Concentration/mM Filgotinib 5.0 420.5 10MDI-2 3.3 552.24 10 MDI-201 2.0 554.59 10 MDI-202 1.9 471.50 10 MDI-2062.0 503.55 10 MDI-203 1.8 488.57 10 MDI-204 2.1 567.63 10 MDI-205 1.9549.64 10 MDI-207 1.5 455.50 10 MDI-209 1.9 431.47 10 MDI-211 1.6 445.5010 MDI-213 1.5 461.50 10 MDI-217 1.6 461.54 10

2.2.2 Kinase Reaction Experiment Procedure

2.2.2.1 JAK1 & JAK2 Kinase Reaction Experimental Procedure

a) Dilute Filgotinib (10 mM stock solution) by 10 times, and dilute acompound solution to be tested by 10 times with 100% DMSO, and thenperform a series of dilutions at a ratio of 1:3 in a 384-well dilutionplate (Labcyte, PP-0200). Concentrations of Filgotinib: 1000, 333.33,111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, 0.02, and 0 μM; andconcentrations of the compound to be tested: 1000, 333.33, 111.11,37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, and 0 μM.

b) Use Echo to transfer 0.1 μL of the compound solution to be tested(prepared in step a) to a 384-well reaction plate (PE, 6007290), andcentrifuge it at 1000 rpm/min for 1 min.

c) Transfer 5 μL of kinase (prepared according to 2.2.1.2) to the384-well reaction plate (prepared in step b), centrifuge it at 1000rpm/min for 1 min, and incubate it at 25° C. for 15 min.

d) Transfer 5 μL of the substrate mixture (prepared according to2.2.1.3) to the 384-well reaction plate, centrifuge it at 1000 rpm/minfor 1 min, and incubate it at 25° C. for 60 min. In the reaction system,the final concentrations of Filgotinib are 10, 3.33, 1.11, 0.37, 0.12,0.04, 0.014, 0.0046, 0.0015, 0.0005, and 0 μM. The final concentrationsof the compound to be tested are: 10, 3.33, 1.11, 0.37, 0.12, 0.04,0.014, 0.0046, 0.0015, 0.0005, and 0 μM. The final concentration of DMSOis 1%.

e) Transfer 10 μL of ADP-Glo to the 384-well reaction plate, centrifugeit at 1000 rpm/min for 1 min, and incubate it at 25° C. for 40 min.

f) Transfer 20 μL of Detection solution to the 384-well reaction plate,centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for40 min.

g) Use Envision multi-function plate reader to read the RLU (Relativeluminescence unit) signal. The signal intensity is used to characterizethe degree of kinase activity.

2.2.2.2 JAK3 Kinase Reaction Experimental Procedure

a) Dilute Filgotinib (10 mM stock solution) and a compound solution tobe tested by 10 times with 100% DMSO, and then perform a series ofdilutions at a ratio of 1:3 in a 384-well dilution plate (Labcyte,PP-0200). Filgotinib concentrations are: 10000, 3333.33, 1111.11,370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0.51, 0.17, and 0 μM; andconcentrations of the compound to be tested are: 1000, 333.33, 111.11,37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, and 0 μM.b) Use Echo to transfer 0.1 μL of the compound solution to be tested(prepared in step a) to a 384-well reaction plate (PE, 6007290), andcentrifuge it at 1000 rpm/min for 1 min.c) Transfer 5 μL of kinase (prepared according to 2.2.1.2) to the384-well reaction plate (prepared in step b), centrifuge it at 1000rpm/min for 1 min, and incubate it at 25° C. for 15 min.d) Transfer 5 μL of the substrate mixture (prepared according to2.2.1.3) to the 384-well reaction plate, centrifuge it at 1000 rpm/minfor 1 min, and incubate it at 25° C. for 60 min. In the reaction system,the final concentrations of Filgotinib are 100, 33.33, 11.11, 3.70,1.23, 0.412, 0.137, 0.046, 0.015, 0.005, 0.002, and 0 μM. The finalconcentrations of the compound to be tested are: 10, 3.33, 1.11, 0.37,0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, and 0 μM. The finalconcentration of DMSO is 1%.e) Transfer 10 μLADP-Glo to the 384-well reaction plate, centrifuge itat 1000 rpm/min for 1 min, and incubate it at 25° C. for 40 min.f) Transfer 20 μL of Detection solution to the 384-well reaction plate,centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for40 min.g) Use Envision multi-function plate reader to read the RLU (Relativeluminescence unit) signal. The signal intensity is used to characterizethe degree of kinase activity.

2.2.2.3 TYK2 Kinase Reaction Experimental Procedure

a) Dilute Filgotinib (10 mM stock solution) by 3.3 times, and a compoundsolution to be tested by 10 times with 100% DMSO, and then perform aseries of dilutions at a ratio of 1:3 in a 384-well dilution plate(Labcyte, PP-0200). The concentrations of Filgotinib are: 3000, 1000,333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, and 0 μM;and the concentrations of the compound to be tested are: 1000, 333.33,111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, and 0 μM.

b) Use Echo to transfer 0.1 μL of the compound solution to be tested(prepared in step a) to a 384-well reaction plate (PE, 6007290), andcentrifuge it at 1000 rpm/min for 1 min.

c) Transfer 5 μL of kinase (prepared according to 2.2.1.2) to the384-well reaction plate (prepared in step b), centrifuge it at 1000rpm/min for 1 min, and incubate it at 25° C. for 15 min.

d) Transfer 5 μL of the substrate mixture (prepared according to2.2.1.3) to the 384-well reaction plate, centrifuge it at 1000 rpm/minfor 1 min, and incubate it at 25° C. for 60 min. In the reaction system,the final concentrations of Filgotinib are 30, 10, 3.3333, 1.1111,0.3704, 0.1235, 0.0412, 0.0137, 0.0046, 0.0015, 0.0005, and 0 μM. Thefinal concentrations of the compound to be tested are: 10, 3.33, 1.11,0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, and 0 μM. The finalconcentration of DMSO is 1%.

e) Transfer 10 μL of ADP-Glo to the 384-well reaction plate, centrifugeit at 1000 rpm/min for 1 min, and incubate it at 25° C. for 40 min.

f) Transfer 20 μL of Detection solution to the 384-well reaction plate,centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for40 min.

g) Use Envision multi-function plate reader to read the RLU (Relativeluminescence unit) signal. The signal intensity is used to characterizethe degree of kinase activity.

2.2.3 Experimental Data Processing Method

Compound inhibition rate (% inh)=(negative control−compound)/(negativecontrol-positive control)*100%

Negative control: DMSO

Positive control: 10 μM/100 μM/30 μM Filgotinib

IC50 (half inhibitory concentration) of the compound can be obtainedusing the following nonlinear fitting formula:

Y=Bottom+(Top-Bottom)/(1+10{circumflex over ( )}((LogIC50-X)*HillSlope))

X: log value of the compound concentration

Y: Compound inhibition rate (% inh)

Z′ Factor Calculation Equation:

Z′=1−3(SD min+SD max)/(AVE max−AVE min)

in which:Min is the RLU value of the positive control 10 μM/100 μM/30 μMFilgotinib, and Max is the RLU value of the negative control; andSD is the standard error, and AVE is the average value of RLU.

3. Experimental Results

3.1 Quality Control Results of Binding Experiment

3.1.1 Quality Control Result of JAK1 Binding Experiment

Z′=0.77CV % (min)=0% CV % (max)=6.2%

3.1.2 Quality Control Result of JAK2 Binding Experiment

Z′=0.78CV % (min)=2.9% CV % (max)=5.7%

3.1.3 Quality Control Result of JAK3 Binding Experiment

Z′=0.71CV % (min)=7.0% CV % (max)=11.3%

3.1.4 Quality Control Result of TYK2 Binding Experiment

Z′=0.77CV % (min)=3.9% CV % (max)=6.8%

3.2 Summary of Test Results as Obtained

Item Tested compound Hillslope IC50 (nM) JAK1 Filgotinib 1.067 25.550Experiment MDI-2 1.356 0.8056 MDI-201 3.487 0.138 MDI-202 5.052 0.125MDI-206 1.091 0.943 JAK2 Filgotinib 1.142 67.920 Experiment MDI-2 1.2710.7723 MDI-201 1.633 0.217 MDI-202 2.385 0.279 MDI-206 1.457 0.556 JAK3Filgotinib 1.318 1343 Experiment MDI-2 1.569 0.7649 MDI-201 1.989 0.187MDI-202 2.038 0.160 MDI-206 1.216 0.628 TYK2 Filgotinib 1.037 128.0Experiment MDI-2 1.630 MDI-201 1.411 0.281 MDI-202 1.416 0.318 MDI-2060.744 7.229

For brevity, only IC50 values are shown for the below tested compounds.

Item Tested compound IC50 (nM) JAK1 Experiment Filgotinib 25.550 MDI-2030.160 MDI-204 0.152 MDI-205 0.121 MDI-207 0.120 MDI-209 0.128 MDI-2110.162 MDI-213 0.146 MDI-217 0.122 JAK2 Experiment Filgotinib 67.920MDI-203 0.208 MDI-204 0.176 MDI-205 0.158 MDI-207 0.160 MDI-209 0.165MDI-211 0.198 MDI-213 0.166 MDI-217 0.217 JAK3 Experiment Filgotinib1343 MDI-203 0.212 MDI-204 0.238 MDI-205 0.178 MDI-207 0.132 MDI-2090.158 MDI-211 0.160 MDI-213 0.116 MDI-217 0.137 TYK2 ExperimentFilgotinib 128.0 MDI-203 0.328 MDI-204 0.200 MDI-205 0.194 MDI-207 0.474MDI-209 0.281 MDI-211 0.266 MDI-213 0.146 MDI-217 0.391

The above experimental results demonstrate that: MDI-2, MDI-201,MDI-202, MDI-206, MDI-203, MDI-204, MDI-207, MDI-209, MDI-211, MDI-213,and MDI-217 can inhibit JAK1, JAK2, JAK3, and TYK2 at an extremely lowconcentration, and the inhibitory activities of the compounds in theseexamples are much higher than that of Filgotinib.

Example 60: Evaluation II of Pharmacological Activity

1. Experimental Principle

The experimental principle of the pharmacological activity evaluation inthis example is the same as that described in Example 59, but theexperimental materials or instruments as used, and/or some specific testcondition parameters (such as the kinase formulation, substrateformulation, kinase reaction experiment procedures, and the like) werevaried and adjusted.

2. Experimental Scheme

2.1 Experimental Materials and Instruments

No. Name Source/Supplier Catalogue No.  1 HEPES Life 15630-080Technologies  2 BRIJ 35 detergent (10%) Sigma 1018940100  3 MgCl2 SigmaM1028  4 EGTA Sigma E3889  5 ADP-Glo Kinase Assay Promega V9101  6 JAK1Carna 08-144  7 JAK2 Carna 08-045  8 JAK3 Carna 08-046  9 TYK2 Carna08-147 10 ATP Promega V915B 11 IRS1 Signalchem 140-58-1000 12 IGF1RtideSignalchem 115-58 13 Poly (4:1 Glu, Tyr) Sigma P0275 15 384-Wellpolystyrene shallow Greiner 784075 flat white 16 384-Well Polypropylenemicroplate Labcyte PP-0200 17 Biotek Microplate Reader Biotek Synergy 418 Microplate Low Speed Centrifuge XiangZhi TD5B

2.2 Experimental Methods

2.2.1 Kinase Reaction Reagent Formulation

2.2.1.1 1× Kinase Reaction Buffer (400 mL)

It was the same as the formulation of the 1× kinase reaction buffer inExample 59.

2.2.1.2 2× Kinase Formulation

JAK1 kinase solution Stock 2X Final Final Name concentration VolumeConcentration Concentration JAK1 3225 nM 5.21 μL 40 nM 20 nM 1X Kinase(884X) 414.79 μL Reaction Buffer

JAK2 kinase solution Stock 2X Final Final Name concentration VolumeConcentration Concentration JAK2 4256 nM 0.2 μL 2 nM 1 nM (4955X) 1XKinase 419.8 μL Reaction Buffer

JAK3 kinase solution Stock 2X Final Final Name concentration VolumeConcentration Concentration JAK3 3195 nM 0.5 μL 4 nM 2 nM (5341.2X) 1XKinase 419.5 μL Reaction Buffer

TYK2 kinase solution Stock 2X Final Final Name concentration VolumeConcentration Concentration TYK2 3174 nM 2.65 μL 20 nM 10 nM (763X) 1XKinase 417.35 μL Reaction Buffer

2.2.1.3 4× Substrate Mixture Formulation

JAK1 substrate mixture solution Stock 4X Final Final Name concentrationVolume Concentration Concentration ATP 10 mM 2.4 μL 80 μM 20 μM (125X)IRS1 1 mg/mL 60 μL 0.2 mg/mL 0.05 mg/mL 1X Kinase (5X) 237.6 μL ReactionBuffer

JAK2 substrate mixture solution Stock 4X Final Final Name concentrationVolume Concentration Concentration ATP 10 mM 6 μL 20 μM 5 μM (500X)IGF1Rtide 1 mg/mL 12 μL 0.04 mg/mL 0.01 mg/mL (25X) 1X Kinase 287.4 μLReaction Buffer

JAK3 substrate mixture solution Stock 4X Final Final Name concentrationVolume Concentration Concentration ATP 10 mM 1.2 μL 40 μM 10 μM (250X)Poly 5 mg/mL 6 μL 0.12 mg/mL 0.03 mg/mL (4:1 Glu, Tyr) (41.6X) Peptide1X Kinase 292.8 μL Reaction Buffer

TYK2 substrate mixture solution Stock 4X Final Final Name concentrationVolume Concentration Concentration ATP 10 mM 1.2 μL 40 μM 10 μM (250X)IRS1 1 mg/mL 60 μL 0.08 mg/mL 0.02 mg/mL (5X) 1X Kinase 238.8 μLReaction Buffer

2.2.1.4 Compounds to be Tested

Name Mass/mg Molecular weight Concentration/mM Filgotinib 5.0 420.5 10MDI-208 1.6 417.49 10 MDI-210 1.4 431.52 10 MDI-214 1.5 469.48 10MDI-215 1.5 469.48 10 MDI-218 1.5 467.52 10 MDI-219 1.7 481.55 10MDI-220 1.5 495.57 10 MDI-221 1.5 457.51 10 MDI-224 1.5 431.52 10MDI-225 1.6 447.51 10 MDI-216 1.5 476.51 10 MDI-226 1.7 405.43 10MDI-227 1.6 419.46 10 MDI-228 1.5 433.49 10 MDI-229 1.5 445.50 10MDI-230 1.4 447.51 10 MDI-233 1.6 474.54 10 MDI-235 1.8 489.56 10MDI-231 1.5 460.51 10 MDI-232 1.8 446.49 10 MDI-234 1.5 476.51 10MDI-236 1.8 503.58 10 MDI-237 2.3 432.5 10 MDI-239 1.5 445.5 10 MDI-2401.6 490.5 10 MDI-242 1.4 432.5 10 MDI-243 1.7 476.5 10 MDI-244 1.8 462.510 MDI-245 1.6 490.5 10 MDI-246 1.5 420.5 10 MDI-247 1.8 434.5 10MDI-248 1.5 450.5 10 MDI-249 1.9 471.5 10 MDI-250 1.6 485.5 10 MDI-2512.1 476.5 10 MDI-252 1.8 421.4 10 MDI-253 1.6 435.5 10 MDI-255 1.4 477.510 MDI-256 1.4 430.4 10 MDI-257 1.6 434.5 10 MDI-258 1.5 459.5 10MDI-259 1.7 446.5 10 MDI-260 1.7 460.5 10 MDI-261 1.6 487.5 10 MDI-2621.7 460.5 10 MDI-263 1.3 460.5 10

2.2.2 Kinase Reaction Experiment Procedure

2.2.2.1 JAK1 & JAK2 Kinase Reaction Experimental Procedure

a) Dilute a compound solution to be tested by 5 times with 100% DMSO.Then, using 100% DMSO as diluent, perform a series of dilutions at aratio of 1:3 for Filgotinib (10 mM stock solution) and the compoundsolution to be tested in a 96-well dilution plate. Take out 1 μL of thecompound solution and add it to 49 μL of kinase reaction buffer, andshake the resulting mixture on a microplate shaker for 20 minutes.b) Transfer 2 μL of kinase (prepared according to 2.2.1.2) to a 384-wellreaction plate, add 1 μL of the compound solution to be tested (preparedin step a) to the 384-well reaction plate (Greiner, 784075), centrifugeit at 1000 rpm/min for 1 min and incubate it at 25° C. for 10 min.c) Transfer 1 μL of the substrate mixture (prepared according to2.2.1.3) to the 384-well reaction plate, centrifuge it at 1000 rpm/minfor 1 min, and incubate it at 25° C. for 60 min. In the reaction system,the final concentrations of Filgotinib are 50, 12.5, 3.125, 0.7812,0.1953, 0.0488, 0.0122, 0.003, 0.00076, 0.00019, and 0.000047 μM. Thefinal concentrations of the compound to be tested are: 10, 2.5, 0.625,0.15625, 0.039, 0.0097, 0.0024, 0.0006, 0.0015, 0.000038, and 0.0000095μM. The final concentration of DMSO is 0.5%.d) Transfer 4 μL of ADP-Glo to the 384-well reaction plate, centrifugeit at 1000 rpm/min for 1 min, and incubate it at 25° C. for 40 min.e) Transfer 8 μL of Detection solution to the 384-well reaction plate,centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for40 min.f) Use Biotek multi-function plate reader to read the RLU (Relativeluminescence unit) signal. The signal intensity is used to characterizethe degree of kinase activity.

2.2.2.1 JAK3 & TYK2 Kinase Reaction Experimental Procedure

a) Dilute a compound solution to be tested by 5 times with 100% DMSO.Then, using 100% DMSO as diluent, perform a series of dilutions at aratio of 1:3 for Filgotinib (10 mM stock solution) and the compoundsolution to be tested in a 96-well dilution plate. Take out 1 μL of thecompound solution and add it to 49 μL of kinase reaction buffer, andshake the resulting mixture on a microplate shaker for 20 minutes.b) Transfer 2 μL of kinase (prepared according to 2.2.1.2) to a 384-wellreaction plate, and add 1 μL of the compound solution to be tested(prepared in step a) to the 384-well reaction plate (Greiner, 784075),centrifuge it at 1000 rpm/min for 1 min and incubate it at 25° C. for 10min.c) Transfer 1 μL of the substrate mixture (prepared according to2.2.1.3) to the 384-well reaction plate, centrifuge it at 1000 rpm/minfor 1 min, and incubate it at 25° C. for 60 min. In the reaction system,the final concentrations of Filgotinib are 50, 16.67, 5.555, 1.851,0.617, 0.205, 0.0686, 0.0228, 0.00762, and 0.0025 μM. The finalconcentrations of the compound to be tested are 10, 3.33, 1.11, 0.37,0.12, 0.04, 0.014, 0.0046, 0.0015, and 0.0005 μM. The finalconcentration of DMSO is 0.5%.d) Transfer 4 μL of ADP-Glo to the 384-well reaction plate, centrifugeit at 1000 rpm/min for 1 min, and incubate it at 25° C. for 40 min.e) Transfer 8 μL of Detection solution to the 384-well reaction plate,centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for40 min.f) Use Biotek multi-function plate reader to read the RLU (Relativeluminescence unit) signal. The signal intensity is used to characterizethe degree of kinase activity.

2.2.3 Experimental Data Processing Method

The same as the experimental data processing method used in Example 59.

3. Experimental Results

Item Tested Compound IC50 (nM) JAK1 Experiment Filgotinib 88 MDI-2080.153 MDI-210 0.347 MDI-214 0.303 MDI-215 0.197 MDI-218 0.825 MDI-2191.38 MDI-220 2.02 MDI-221 0.128 MDI-224 0.248 MDI-225 0.226 MDI-2160.134 MDI-226 0.308 MDI-227 0.224 MDI-228 0.398 MDI-229 0.753 MDI-2300.819 MDI-233 1.31 MDI-235 0.0395 MDI-231 0.530 MDI-232 0.745 MDI-2340.206 MDI-236 0.0403 JAK2 Experiment Filgotinib 71 MDI-208 0.440 MDI-2101.11 MDI-214 0.273 MDI-215 0.277 MDI-218 0.614 MDI-219 1.38 MDI-220 1.38MDI-221 0.363 MDI-224 0.754 MDI-225 0.390 MDI-216 0.233 MDI-226 0.371MDI-227 0.246 MDI-228 0.355 MDI-229 0.356 MDI-230 0.555 MDI-233 1.33MDI-235 0.166 MDI-231 1.17 MDI-232 1.04 MDI-234 0.737 MDI-236 0.329 JAK3Experiment Filgotinib 1463 MDI-208 1.11 MDI-210 0.979 MDI-214 0.352MDI-215 0.308 MDI-218 0.948 MDI-219 2.29 MDI-220 3.15 MDI-221 0.379MDI-224 2.01 MDI-225 0.487 MDI-216 0.247 MDI-226 0.676 MDI-227 0.441MDI-228 0.565 MDI-229 0.481 MDI-230 0.821 MDI-233 2.60 MDI-235 0.183MDI-231 0.893 MDI-232 0.868 MDI-234 0.375 MDI-236 0.141 TYK2 ExperimentFilgotinib 532 MDI-208 9.31 MDI-210 31.5 MDI-214 2.8 MDI-215 1.58MDI-218 1.75 MDI-219 1.88 MDI-220 5.56 MDI-221 7.60 MDI-224 16.1 MDI-2253.50 MDI-216 1.62 MDI-226 4.18 MDI-227 3.89 MDI-228 4.76 MDI-229 4.71MDI-230 6.57 MDI-233 3.50 MDI-235 0.142 MDI-231 1.31 MDI-232 2.26MDI-234 0.438 MDI-236 0.0954 JAK1 Experiment Filgotinib 46.2 MDI-2370.758 MDI-239 1.15 MDI-240 0.450 MDI-242 67.2 MDI-243 0.118 MDI-2440.248 MDI-245 0.178 MDI-246 0.241 MDI-247 0.557 MDI-248 0.093 MDI-2490.307 MDI-250 0.395 MDI-251 0.144 MDI-252 1.8 MDI-253 2.9 MDI-255 57.2MDI-256 0.700 MDI-257 0.185 MDI-258 0.939 MDI-259 0.659 MDI-260 2.28MDI-261 0.154 MDI-262 0.319 MDI-263 0.120 JAK2 Experiment Filgotinib47.6 MDI-237 0.588 MDI-239 1.20 MDI-240 0.842 MDI-242 28.6 MDI-243 0.499MDI-244 0.915 MDI-245 0.648 MDI-246 0.973 MDI-247 1.88 MDI-248 0.560MDI-249 0.697 MDI-250 0.974 MDI-251 0.818 MDI-252 2.6 MDI-253 1.6MDI-255 37.4 MDI-256 3.06 MDI-257 0.600 MDI-258 3.31 MDI-259 1.30MDI-260 2.99 MDI-261 0.703 MDI-262 1.54 MDI-263 0.717 JAK3 ExperimentFilgotinib 1051 MDI-237 1.39 MDI-239 4.94 MDI-240 2.02 MDI-242 152MDI-243 0.269 MDI-244 0.550 MDI-245 0.306 MDI-246 0.709 MDI-247 1.30MDI-248 0.303 MDI-249 0.398 MDI-250 0.497 MDI-251 0.406 MDI-252 2.2MDI-253 1.5 MDI-256 2.71 MDI-257 0.381 MDI-258 2.36 MDI-259 1.29 MDI-2602.47 MDI-261 0.473 MDI-262 1.22 MDI-263 0.458 TYK2 Experiment Filgotinib233 MDI-237 9.68 MDI-239 19.2 MDI-240 5.34 MDI-242 583 MDI-243 0.167MDI-244 1.31 MDI-245 0.365 MDI-246 1.52 MDI-247 2.35 MDI-248 0.578MDI-249 1.93 MDI-250 0.993 MDI-251 1.33 MDI-252 22 MDI-253 31 MDI-2566.14 MDI-257 0.684 MDI-258 6.27 MDI-259 2.94 MDI-260 8.98 MDI-261 1.16MDI-262 2.59 MDI-263 0.717

The above experimental results show that among the compounds of thepresent disclosure tested in Example 60, except that few examplecompound has a comparable activity as Filgotinib, most of the testedcompounds can inhibit JAK1, JAK2, JAK3, and TYK3 at very lowconcentrations and the inhibitory activities of these compounds are muchhigher than that of Filgotinib.

Although specific embodiments of the present disclosure have beenillustrated and described, it does not mean that these embodimentsillustrate and describe all possible implementation forms of the presentdisclosure. More precisely, the language used in this specification areonly descriptive words and not restrictive. It will be obvious to thoseskilled in the art that various kinds of changes and modifications canbe made without departing from the general scope of the presentdisclosure. Therefore, the appended claims are intended to include allthese changes and modifications within the scope of the presentdisclosure.

What is claimed is:
 1. A compound of Formula (G),

or an isotopically labeled compound thereof, or an optical isomerthereof, a geometric isomer thereof, a tautomer thereof or a mixture ofvarious isomers, or a pharmaceutically acceptable salt thereof, or aprodrug thereof, or a metabolite thereof, in which L is C═O, O═S═O, CH₂or a linkage; and X₁ is N or CR₁₄; and X₂ is N or CR₁₅; and X₃ is N orCR₁₆; and R₁₄, R₁₅, R₁₆ are each independently selected from H, —OH,—SH, —CN, halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂, —C(═O)—OR₁₂,—OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, inwhich the —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, and3-7 membered heterocycloalkyl are optionally substituted with 1, 2 or 3substitutes selected from halogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN,C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄ hydroxyalkyl, —S—C₁₋₄ alkyl, —C(═O)H,—C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄ alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄alkyl)₂, —N(C₁₋₄ alkyl)(C(═O) C₁₋₄ alkyl), C₁₋₄ haloalkyl, C₁₋₄ alkoxyand C₁₋₄ haloalkoxy; and R₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —SR₁₂,—OR₁₂, —CN, halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl or C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl,11-15 membered tricyclyl, C₅₋₁₁bicycloalkyl, or 5-11 membered bicyclicheteroalkyl, and R₁₃ is substituted with 0, 1, 2, 3 or 4 R₁(s), in whichR₁₇, and R₁₈ are each independently selected from H, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15memberedtricyclyl, C₅₋₁₁bicycloalkyl, and 5-11 membered bicyclic heteroalkyl andare optionally substituted with one or more substitutes eachindependently selected from —OH, —CN, —SH, halogen, —NO₂, —SF₅, —S—C₁₋₄alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclicheteroaryl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀),—C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂),—S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, wherein the —S—C₁₋₄ alkyl, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclic heteroarylare optionally substituted with 1, 2 or 3 substitutes each independentlyselected from halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂; or R₁₇, R₁₈ andthe N atom connected thereto together form a 3-14 membered ring; and 0,1, 2, 3 or 4 R₂(s) are present in formula (G), and R₂ is selected fromH, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,4-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl,C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂, —C(═O)—OR₁₂,—OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, inwhich the —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl,C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11membered bicyclic heteroaryl are each optionally substituted with 1, 2or 3 substituent(s) each independently selected from the groupconsisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂; and R₁ isselected from H, halogen, —OH, —NO₂, —CN, —SF₅, —SH, —S—C₁₋₄ alkyl, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₃₋₇ cycloalkyl, 3-10membered heterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15memberedtricyclyl, C₅₋₁₁bicycloalkyl, 5-11 membered bicyclic heteroalkyl,—N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀), —C(═O)—R₁₂,—C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂and —OR₁₂, in which the —S—C₁₋₄ alkyl, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, and C₁₋₈ alkoxy are optionally substituted with 1, 2, 3, or 4R₃(s), and in which the C₃₋₇ cycloalkyl, 3-10 membered heterocycloalkyl,C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11membered bicyclic heteroaryl are optionally substituted with 1, 2, 3, or4 R₄(s); and R₃ and R₄ are each independently selected from H, halogen,—OH, —NO₂, —CN, —SF₅, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 3-10 membered heterocycloalkyl,C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 memberedbicyclic heteroaryl, —N(R₅)(R₆), —N(R₁₁)(C(═O)R₁₂), —CON(R₇)(R₈),—C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂),—S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the C₁₋₆ alkyl, C₃₋₇cycloalkyl, 3-10 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclic heteroarylare each optionally substituted with 1, 2, 3 or 4 substituent(s) eachindependently selected from the group consisting of halogen, —CN, —OH,C₁₋₄ alkyl, C₁₋₆ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆cycloalkyl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H,—C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀), —N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀),—SR₁₂ and —OR₁₂; and R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ are eachindependently H or selected from the group consisting of C₁₋₆ alkyl,C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, 4-14 membered heterocycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and(5-10 membered heteroaryl)-C₁₋₄ alkyl-, wherein the substituentsincluded in the above group are each optionally substituted with 1, 2, 3or 4 substituent(s) each independently selected from the groupconsisting of halogen, —CF₃, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, oxo,C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₄hydroxyalkyl, —S—C₁₋₄ alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxyand C₁₋₄ haloalkoxy.
 2. The compound, or an isotopically labeledcompound thereof, or an optical isomer thereof, a geometric isomerthereof, a tautomer thereof or a mixture of various isomers, or apharmaceutically acceptable salt thereof, or a prodrug thereof, or ametabolite thereof according to claim 1, which is an isotopicallylabeled compound of the compound of formula (G), wherein all Hs are eachindependently and optionally substituted with D.
 3. The compound, or anisotopically labeled compound thereof, or an optical isomer thereof, ageometric isomer thereof, a tautomer thereof or a mixture of variousisomers, or a pharmaceutically acceptable salt thereof, or a prodrugthereof, or a metabolite thereof according to claim 1, wherein X₁ isCR₁₄, X₂ is N or CR₁₅, and X₃ is CR₁₆.
 4. The compound, or anisotopically labeled compound thereof, or an optical isomer thereof, ageometric isomer thereof, a tautomer thereof or a mixture of variousisomers, or a pharmaceutically acceptable salt thereof, or a prodrugthereof, or a metabolite thereof according to claim 1, wherein X₁, X₂and X₃ are CH.
 5. The compound, or an isotopically labeled compoundthereof, or an optical isomer thereof, a geometric isomer thereof, atautomer thereof or a mixture of various isomers, or a pharmaceuticallyacceptable salt thereof, or a prodrug thereof, or a metabolite thereofaccording to claim 1, wherein L is C═O, O═S═O or CH₂.
 6. The compound,or an isotopically labeled compound thereof, or an optical isomerthereof, a geometric isomer thereof, a tautomer thereof or a mixture ofvarious isomers, or a pharmaceutically acceptable salt thereof, or aprodrug thereof, or a metabolite thereof according to claim 1, whereinR₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —OH, —SH, —CN, halogen, —NO₂, —SF₅,—S—C₁₋₄ alkyl, C₁₋₆ alkyl, or C₃₋₇ cycloalkyl, 3-7 memberedheterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁ bicyclicaryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclyl,C₅₋₁₁bicycloalkyl, or 5-11 membered bicyclic heteroalkyl, and R₁₃ issubstituted with 0, 1, 2, 3 or 4 R₁(s), in which R₁₇ and R₁₈ are eachindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₅₋₇ aryl, and 5-7 membered heteroaryl, and areoptionally substituted with one or more of —OH, —CN, —SH, halogen,—NO₂,— and SF₅.
 7. The compound, or an isotopically labeled compoundthereof, or an optical isomer thereof, a geometric isomer thereof, atautomer thereof or a mixture of various isomers, or a pharmaceuticallyacceptable salt thereof, or a prodrug thereof, or a metabolite thereofaccording to claim 1, wherein R₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, —OH,—SH, —CN, halogen, —NO₂, —SF₅, —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₃₋₇cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7 memberedheteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclic heteroaryl, or11-15 membered tricyclyl, and R₁₃ is substituted with 0, 1, 2, 3 or 4R₁(s).
 8. The compound, or an isotopically labeled compound thereof, oran optical isomer thereof, a geometric isomer thereof, a tautomerthereof or a mixture of various isomers, or a pharmaceuticallyacceptable salt thereof, or a prodrug thereof, or a metabolite thereofaccording to claim 1, wherein R₁₃ is H, —N(R₁₇)(R₁₈), C₁₋₆ alkoxy, C₁₋₆alkyl, C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, or 5-7membered heteroaryl, and R₁₃ is substituted with 0, 1, 2, 3, or 4 R₁(s).9. The compound, or an isotopically labeled compound thereof, or anoptical isomer thereof, a geometric isomer thereof, a tautomer thereofor a mixture of various isomers, or a pharmaceutically acceptable saltthereof, or a prodrug thereof, or a metabolite thereof according toclaim 1, wherein R₁₇ and R₁₈ are each independently selected from H,C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₃₋₇ heterocycloalkyl, and areoptionally substituted with one or more of —OH, —CN, —SH, halogen, —NO₂,and SF₅.
 10. The compound, or an isotopically labeled compound thereof,or an optical isomer thereof, a geometric isomer thereof, a tautomerthereof or a mixture of various isomers, or a pharmaceuticallyacceptable salt thereof, or a prodrug thereof, or a metabolite thereofaccording to claim 1, wherein L is C═O, and R₁₃ is —N(R₁₇)(R₁₈), C₁₋₆alkoxy, —OH, —SH, —CN, halogen, —NO₂, —SF₅, or —S—C₁₋₄ alkyl, and R₁₃ issubstituted with 0, 1, 2, 3 or 4 R₁(s) in which R₁₇ and R₁₈ are eachindependently selected from H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl,C₃₋₇ heterocycloalkyl, C₅₋₇ aryl, and 5-7 membered heteroaryl, and areoptionally substituted with one or more of —OH, —CN, —SH, halogen,—NO₂,— and SF₅, or R₁₇, R₁₈ and the N atom connected thereto togetherform a 3-14 membered ring.
 11. The compound, or an isotopically labeledcompound thereof, or an optical isomer thereof, a geometric isomerthereof, a tautomer thereof or a mixture of various isomers, or apharmaceutically acceptable salt thereof, or a prodrug thereof, or ametabolite thereof according to claim 1, wherein 1, 2 or 3 R₂(s) arepresent and R₂ is selected from H, halogen, —OH, —NO₂, —CN, —SF₅, —SH,—S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, and 4-10 membered heterocycloalkyl, inwhich the —S—C₁₋₄ alkyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2 or 3substituent(s) each independently selected from the group consisting ofhalogen, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxy, and C₁₋₄ haloalkoxy.
 12. The compound, or an isotopicallylabeled compound thereof, or an optical isomer thereof, a geometricisomer thereof, a tautomer thereof or a mixture of various isomers, or apharmaceutically acceptable salt thereof, or a prodrug thereof, or ametabolite thereof according to claim 1, wherein 1, 2 or 3 R₂(s) arepresent, and R₂ is selected from halogen, C₁₋₆ alkyl, and C₃₋₆cycloalkyl, in which the C₁₋₆ alkyl and C₃₋₆ cycloalkyl are eachoptionally substituted with 1, 2 or 3 substituent(s) each independentlyselected from the group consisting of halogen, —OH, —NH₂, —NH(CH₃),—N(CH₃)₂, —CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy.
 13. The compound, or an isotopically labeled compoundthereof, or an optical isomer thereof, a geometric isomer thereof, atautomer thereof or a mixture of various isomers, or a pharmaceuticallyacceptable salt thereof, or a prodrug thereof, or a metabolite thereofaccording to claim 1, wherein 1 or 2 R₂(s) are present, and R₂ isselected from halogen, and C₁₋₆ alkyl.
 14. The compound, or anisotopically labeled compound thereof, or an optical isomer thereof, ageometric isomer thereof, a tautomer thereof or a mixture of variousisomers, or a pharmaceutically acceptable salt thereof, or a prodrugthereof, or a metabolite thereof according to claim 1, wherein R₁₃ issubstituted with 0 or 1 R₁, and R₁ is selected from halogen, —OH, C₁₋₆alkyl, 5-7 membered heterocycloalkyl, and C₃₋₇ cycloalkyl, in which theC₁₋₆ alkyl is optionally substituted with 1,2, or 3 R₃(s) and in whichthe 5-7 membered heterocycloalkyl, and C₃₋₇ cycloalkyl is optionallysubstituted with 1, 2, 3 or 4 C₁₋₃ alkyl.
 15. The compound, or anisotopically labeled compound thereof, or an optical isomer thereof, ageometric isomer thereof, a tautomer thereof or a mixture of variousisomers, or a pharmaceutically acceptable salt thereof, or a prodrugthereof, or a metabolite thereof according to claim 1, wherein thecompound is a compound of Formula (I),

or an isotopically labeled compound thereof, or an optical isomerthereof, a geometric isomer thereof, a tautomer thereof or a mixture ofvarious isomers, or a pharmaceutically acceptable salt thereof, or aprodrug thereof, or a metabolite thereof, in which L is C═O, O═S═O, CH₂or a linkage; and X is CH or N; the ring A is C₃₋₇ cycloalkyl, 3-7membered heterocycloalkyl, C₅₋₇ aryl, 5-7 membered heteroaryl, C₇₋₁₁bicyclic aryl, 7-11 membered bicyclic heteroaryl, or 11-15 memberedtricyclyl; 0, 1, 2, 3 or 4 R₁(s) are present in formula (I), and R₁ isselected from H, halogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈alkoxy, C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7membered heteroaryl, C₇₋₁₁ bicyclic aryl, and 7-11 membered bicyclicheteroaryl, in which the C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, andC₁₋₈ alkoxy are optionally substituted with 1, 2, 3 or 4 R₃(s), and inwhich the C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, 5-7membered heteroaryl, C₇₋₁₁ bicyclic aryl, 7-11 membered bicyclicheteroaryl are optionally substituted with 1, 2, 3 or 4 R₄(s), 0, 1, 2,3 or 4 R₂(s) are present in formula (I), and R₂ is selected from H,halogen, —OH, —NO₂, —CN, —SF₅, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-10 memberedheterocycloalkyl, —N(R₉)(R₁₀), —N(R₁₁)(C(═O)R₁₂), —C(═O)—N(R₉)(R₁₀),—C(═O)—R₁₂, —C(═O)—OR₁₂, —OC(═O)R₁₂, —N(R₁₁)(S(═O)₂R₁₂),—S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂, in which the C₁₋₆ alkyl, C₃₋₇cycloalkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2 or 3 substituent(s) each independently selectedfrom the group consisting of halogen, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, —N(R₉)(R₁₀),—N(R₁₁)(C(═O)R₁₂), —C(═O)—OR₁₂, —C(═O)H, —C(═O)R₁₂, —C(═O)—N(R₉)(R₁₀),—N(R₁₁)(S(═O)₂R₁₂), —S(═O)₂—N(R₉)(R₁₀), —SR₁₂ and —OR₁₂; R₃ is selectedfrom halogen, cyano, C₁₋₃ alkyl, hydroxyl, C₁₋₆ alkoxy, —N(R₅)(R₆),—CON(R₇)(R₈) or 3-7 membered heterocycloalkyl, in which the 3-7 memberedheterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R₄(s); R₄is selected from halogen, C₁₋₃ alkyl, hydroxyl, C₁₋₆ alkoxy, —NH₂,—NHCH₃ or —N(CH₃)₂; R₅, R₆, R₇, R₈ are each independently hydrogen orC₁₋₄ alkyl; R₉ is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₃₋₇cycloalkyl; R₁₀ is H or selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₇ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl-and (5-10 membered heteroaryl)-C₁₋₄ alkyl-, wherein each substituentincluded in the above group is optionally substituted with 1, 2, 3 or 4substituent(s) each independently selected from the group consisting of—OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CN, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₁₋₄hydroxyalkyl, —S—C₁₋₄ alkyl, —C(═O)H, —C(═O)—C₁₋₄ alkyl, —C(═O)—O—C₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ alkoxyand C₁₋₄haloalkoxy; R₁₁ is selected from H, C₁₋₄ alkyl and C₃₋₇cycloalkyl; and R₁₂ is selected from the group consisting of C₁₋₆ alkyl,C₃₋₇ cycloalkyl, 4- to 14-membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, (C₃₋₇ cycloalkyl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, (C₆₋₁₀ aryl)-C₁₋₄ alkyl- and (5-10membered heteroaryl)-C₁₋₄ alkyl-, wherein each substituent included inthe above group is optionally substituted with 1, 2 or 3 substituent(s)each independently selected from the group consisting of halogen, —CF₃,—CN, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, oxo, —S—C₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₄ alkoxy andC₁₋₄ haloalkoxy.
 16. The compound, or an isotopically labeled compoundthereof, or an optical isomer thereof, a geometric isomer thereof, atautomer thereof or a mixture of various isomers, or a pharmaceuticallyacceptable salt thereof, or a prodrug thereof, or a metabolite thereofaccording to claim 15, wherein X is CH.
 17. The compound, or anisotopically labeled compound thereof, or an optical isomer thereof, ageometric isomer thereof, a tautomer thereof or a mixture of variousisomers, or a pharmaceutically acceptable salt thereof, or a prodrugthereof, or a metabolite thereof according to claim 15, wherein the ringA is C₃₋₇ cycloalkyl, 3-7 membered heterocycloalkyl, C₅₋₇ aryl, or 5-7membered heteroaryl.
 18. The compound, or an isotopically labeledcompound thereof, or an optical isomer thereof, a geometric isomerthereof, a tautomer thereof or a mixture of various isomers, or apharmaceutically acceptable salt thereof, or a prodrug thereof, or ametabolite thereof according to claim 15, wherein the ring A is 5-6membered heteroaryl, or phenyl.
 19. The compound, or an isotopicallylabeled compound thereof, or an optical isomer thereof, a geometricisomer thereof, a tautomer thereof or a mixture of various isomers, or apharmaceutically acceptable salt thereof, or a prodrug thereof, or ametabolite thereof according to claim 1, wherein the compound isselected from a group consisting of:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinylpyrazin-2-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperzin-1-yl)pyrazin-2-yl)ketone;(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperzin-1-yl)pyrazin-2-yl)ketone;5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone;4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxylcyclobutyl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl) (pyridazin-3-yl)ketone;(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol;5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol;1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one;1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one;1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one;2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one;1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)ketone;Azetidine-1-yl((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperzin-1-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperzin-1-yl)ketone;Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl) (3-hydroxylpyrrolidin-1-yl)ketone;Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone;(R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylazetidine-1-yl)ketone;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxylpiperidin-1-yl)ketone;2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide;2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide;2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)azetidine-3-nitrile;1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidin-3-nitrile;2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;Methyl2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate;Ethyl2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate;(S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone;3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile;2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide;(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(2,6-diazaspiro[3.3]heptan-2-yl)ketone;(S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol;(R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol;-5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidin-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol;5-ethyl-2-fluoro-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol;and3-ethyl-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol.20. A pharmaceutical composition, comprising the compound, or anisotopically labeled compound thereof, or an optical isomer thereof, ageometric isomer thereof, a tautomer thereof or a mixture of variousisomers, or a pharmaceutically acceptable salt thereof, or a prodrugthereof, or a metabolite thereof according to claim 1, and one or morepharmaceutically acceptable carriers, adjuvants or excipients.
 21. Amethod for the treatment and/or prevention of a JAK-related disease ordisorder, the method comprising administering to a patient in needthereof a therapeutically effective amount of the compound, orisotopically labeled compound thereof, or optical isomer thereof,geometric isomer thereof, a tautomer thereof or a mixture of variousisomers, or a pharmaceutically acceptable salt thereof, or a prodrugthereof, or a metabolite thereof according to claim
 1. 22. The methodaccording to claim 21, wherein the JAK-related disease or disorder isselected from the group consisting of arthritis, autoimmune diseases ordisorders, cancer or tumor, diabetes, eye diseases, disorders orconditions, intestinal inflammation, allergies or conditions,neurodegenerative diseases, skin diseases, conditions or disorders,allergies, asthma and other obstructive airway diseases, and transplantrejection.